Drug disposition and pharmacokinetics in the maternal-placental-fetal unit

Pharmac. Ther. Vol. 10, pp. 301 to 328 © Pergamon Press Ltd. 1980. Printed in Great Britain

0163-7258/80/0701~1301505.00/0

Specialist Subject Editor: J. GY. PAPP

DRUG DISPOSITION AND PHARMACOKINETICS IN THE MATERNAL-PLACENTAL-FETAL UNIT

BEATRICE KRAUER,* F. KRAUER* and F. E.

HYTTEN**

*Department of Gynaecology, University Hospital, 20, rue Alcide dentzer, 1205-Geneva, Switzerland **Division of Perinatal Medicine, Clinical Research Centre, Harrow HA 3U J, Middx., UK.

1. INTRODUCTION Pharmacokinetics is concerned with the description of drug absorption, distribution, metabolism and excretion and with the time course of the pharmacological effects that ensue. It involves the application of mathematical techniques in a physiological and pharmacological context (Gibaldi and Levy, 1976). When attempting to describe the mechanisms of drug movement within the maternal-placental-fetal unit in pharmacokinetic terms, it is therefore necessary both to understand the structural and physiological characteristics and to express the time course of drug concentrations in the various parts of the complex system, as mathematical rate processes. Because the intensity of pharmacological effects is related to the drug concentrations in the body, the determination of pharmacokinetic data may be of practical importance and may serve as a basis for the design of dosage regimens and dosage adjustments. Moreover, such data can provide some help in clarifying the problems which may arise from numerous interacting variables and can give some indication of the likelihood and types of drug interactions that may occur. It follows that in clinical practice pharmacokinetic concepts such as biological half-life, drug distribution and the clearance and bioavailability of drugs can be used to describe and predict the time course of drug concentrations as a function of dose and frequency of drug administration, and thereby help to reach the therapeutic goal. Naturally, the final objective of pharmacotherapy is not to obtain a particular drug concentration, but to achieve a desired therapeutic effect which depends on the relations between the so-called drug bioavailability inputs and the pharmacological response outputs (Smolen, 1978). Information on drug disposition and pharmacokinetics in human pregnancy is fragmentary and generally unsatisfactory and there is no drug for which a reasonably complete picture can be presented. Drugs can only be given ethically for a clinical need so that standardized conditions can seldom, if ever, be achieved, and samples of tissue fluids from the product of conception can, in general, only be taken after delivery. Moreover human physiology, particularly in pregnancy, differs in so many respects from that of other species that only human data can be accepted as relevant. For these reasons, this review can do little more than present a blurred and incomplete picture of an immensely complex subject.

2. THE INFLUENCE OF PHYSIOLOGICAL CHANGES IN PREGNANCY It must be said at once that the common assumption by many physicians that for therapeutic purposes the pregnant woman is no more than a non-pregnant woman with a fetus attached is seriously misleading. Every component of pharmacokjnetics is modified, and modified progressively, by the continuous morphological and physiological changes associated with pregnancy (Hytten and Leitch, 1971; Krauer and Krauer, 1977). 301

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BEATRICEKRAUER,F. KRAUERand F. E. HYTTEN 2.1. INGESTION

Pregnancy has a considerable influence on compliance. It is commonplace to find patients, particularly the better educated, who will refuse to take any drug in pregnancy on the grounds that the fetus might be harmed; moreover they may be unwilling to confront the physician with that attitude, so the fact that they accept a prescription is no guarantee that they will swallow the medicine. Other reasons for not taking a drug, or taking it irregularly, are the common symptoms of nausea and heartburn, and vomiting may reject any drug that is taken.

2.2. ABSORPTION

2.2.1. Gastric Function Relatively few drugs are absorbed from the stomach, alcohol and salicylates are the classic examples, and there is no direct evidence that any change in gastric physiology would interfere with their absorption. It is possible however that the reduced secretion and depressed motility might result in tablets lying in a relatively quiet pool of diluted gastric juice containing large amounts of mucous (Parbhoo and Johnston, 1966) so that their disintegration might be prolonged. For the majority of drugs, which are absorbed in the small intestine, reduced gastric motility may have an important effect. The speed with which the stomach empties in pregnancy appears to depend on the nature of its contents. An early study by Hansen (1937) suggested a considerable delay in the emptying of a standard test meal, from a non-pregnant average of 50 min to between 80 and 130 min in pregnancy, and Davison et al. (1970) found a considerable, though not statistically significant delay in the emptying of a water meal. Hunt and Murray (1958) by contrast found no delay in the emptying of a water or saline meal. The evidence is not necessarily contradictory; it may be that the ~duodenal brake' operates to prevent the emptying of contents of high osmolality until they become more dilute, a possibility which would explain the finding of Lind and Hytten (1969) that glucose from a solution of 50 g in 200 ml of water was much more slowly absorbed than glucose from an equivalent meal of mashed potato. Such an effect would also explain the high incidence of nausea following a sugary drink in pregnancy. Whatever the effect of pregnancy there can be no doubt that labour has a profound effect on gastric emptying. In one study which modern ethics would never allow to be repeated, Hirsheimer et al. (1938) gave a barium meal to ten healthy primigravidae in active first stage labour between 5 and 38 hr before delivery. X-rays were taken at hourly intervals with the patient standing; in 4 the stomach was empty in 2hr, in 4 it emptied between 2 and 4 hr, and in the remaining 2 there was a considerable residue after 4 hr, one of them vomiting almost all the meal after delivery at 5 hr. Davison et al. (1970) found the disappearance of a 750ml saline test meal to be tremendously delayed in labour, an average of 445 ml remaining after 30 min compared to 147 ml in normal pregnancy. Nimmo et al. (1975), who used the appearance in the blood of paracetamol after an oral dose as a measure of gastric emptying, showed that the giving of pethidine, diamorphine or pentazocine greatly delayed emptying compared to women not given narcotics in labour. It is the rule in many obstetric units to give antacids throughout labour with a view to minimizing the possible effects of acid aspiration into the mother's lungs in the event of an anaesthetic being given. In Britain and the United States the recommended use of an antacid such as magnesium trisilicate (Crawford, 1977; Roberts and Shirley, 1976) is widely applied. Whether this has any effect on drug absorption has not been investigated but Kutt (1975) has shown that phenytoin absorption is grossly reduced when given in association with antacids which might explain its evident non-absorption in the study by Landon and Kirkley (1979).

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In summary, gastric emptying is delayed in pregnancy particularly if a high osniolality liquid meal is taken, and conspicuously delayed in labour, so that drugs may be erratically absorbed, and may with repeated doses accumulate in the stomach and possibly result in toxic doses when the stomach empties. For medication in labour parenteral administration is essential for effective dosing.

2.2.2. Function of the Small Intestine The small intestine shares the general sluggishness of the gut in pregnancy so that transit time is prolonged, in some cases very considerably (Parry et al., 1970). There is no evidence that this has any influence on drug absorption but in theory slower mixing of intestinal contents could lead to slower and possibly more complete absorption. In conditions where transit time is artificially shortened, as for example after surgical removal of a large amount of small intestine (Montgomery and Pincus, 1955) or following jejuno-ileostomy for the treatment of obesity (Olow et al., 1976), pregnancy may exert a beneficial effect in reducing motility and giving more time for absorption. One other point is worth making. Many pregnant women take regular supplements of iron salts and may have an almost perpetually high iron concentration in the gut contents; salts of aluminium, magnesium and calcium are also commonly taken. These could chelate and interfere with the absorption of drugs such as tetracycline (Neuvonen et al., 1970; Neuvonen, 1976).

2.2.3. Pulmonary Function: Absorption Across the Alveolar Membrane Any substance presented to the respiratory tract in form of a vapour, an aqueous solution or an aerosol will be absorbed by simple diffusion (Curry, 1977) at a rate which is determined mainly by alveolar ventilation and the pulmonary blood flow. Highly lipid soluble substances cross the alveolar membrane almost instantaneously and are rapidly removed from the lungs. Since the alveolar air is almost completely cleared of such substances at each breath, an increase of the respiratory rate would be followed by an increase of the diffusion rate. This s0-called respiration limited diffusion is characteristic of various volatile substances such as ethylene, nitrous oxide, cyclopropane, propylene or acetylene. In contrast, compounds with lower lipid-solubility, such as ethanol, ether, chloroform, halothane or vinylether, equilibrate at a much slower rate, and only a small proportion of such substances is removed from the alveolar air at each breath. This can easily be made up by the next inspiration, without a need of increasing the alveolar ventilation. Increasing the cardiac output however will increase the removal rate of such compounds from the lung, since the pulmonary blood immediately removes all that has crossed the alveolar membrane. Limitation of the diffusion rate by respiration or pulmonary blood flow concerns only volatile or gaseous substances. As far as aerosols are concerned, other factors are of greater importance (Goldstein et al., 1974). Generally, the rate of absorption is much more rapid in the alveolar membrane than anywhere else in the pulmonary tree, but few aerosol particles reach the alveoli. The larger particles tend to impact and to be retained in the upper airways, and very small particles (<0.2 m/~) are retained even higher in the upper airways, probably because diffusion becomes a significant factor in the translocation of such particles from the lumen to the walls of the bronchi and bronchioles. With a normal quiet tidal volume of about 450 ml very few particles of any size reach the alveolar sacs, but by increasing the tidal volume to about 1500 ml, nearly 20 per cent of the particles up to a size of about 5 m/~ may reach the alveolar membrane, and the systemic uptake of compounds dissolved in large aerosol particles may therefore become

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more important. Particle size and airstream velocity are thus limiting factors for the absorption rate of substances dissolved in aerosols. During pregnancy there are characteristic changes of both respiratory and cardiac function: although the vital capacity is not significantly altered in pregnancy, its different components are affected by mechanisms not yet fully understood (Hytten and Leitch, 1971; Alaily and CaroU, 1978; Templeton and Kelman, 1976). Both respiratory minute volume and alveolar ventilation increase from early pregnancy. This change is mainly due to an increase in the tidal volume, which by term has increased by about 40 per cent and by a decrease in the residual lung volume of some 20 per cent; the respiratory rate remains practically unchanged. The distribution of gaseous substances in the alveolar air is thus improved and the mixing of the inspired air with the residual air more effective. Consequently, higher concentrations of volatile compounds may be achieved more rapidly in the alveolar air, and the diffusion rate of highly soluble substances with a respiration-linked equilibration rate may considerably increase. An increase of the tidal volume is normally associated with an increase in the airstream velocity, provided that the airways resistance remains unaltered. Recent measurements of the resistance and the specific conduction of the upper airways, as well as the forced expiratory volume, did not show any significant changes either throughout pregnancy or compared with the non-pregnant state, although pregnancy associated hyperventilation was evident (Milne et al., 1977). Theoretically, therefore, the airstream velocity should increase during pregnancy. The absence of changes in the resistance of the upper airways, however, does not exclude modifications in the peripheral airways. The only technique which has been applied in pregnancy to investigate the smaller airways resistance is the measurement of the lung closing volume. Closing volume has not been shown to change during pregnancy, but the results obtained by this method have a high variability and further studies are needed. Whether the airstream velocity changes during pregnancy remains still unanswered. The reduced alveolar CO2 in pregnancy which follows the physiological hyperventilation might be expected to have a broncho-constricting effect increasing the airway resietance. On the other hand, progesterone, which has a fl2-adrenergic, broncho-dilator effect, may act as an antagonist. This antagonism could explain why the airway resistance does not seem to be altered during pregnancy. The increase in airstream velocity will affect the behaviour of inhaled aerosol particles in pregnant women. Increased particle uptake and increased diffusion should be expected from aerosols such as bronchodilatators, local anaesthetics, antimicrobial and disinfectant agents, oxytocics, particles in polluted air, cosmetics, industrial sprays, paints, dust, pollen, smoke (including cannabis) and radioactive substances. This theory needs experimental confirmation. Early in pregnancy the cardiac output increases by about 30 per cent due to an increase in both heart rate and stroke volume. No change has been found in the physiological A-V-shunt (Hytten and Leitch, 1971; Templeton, 1976). (See also 2.3.4.) As discussed above, cardiac output and pulmonary blood flow can influence the equilibration rate of volatile substances, and tissue concentrations may rise more quickly, especially in those organs with a high blood perfusion rate, such as, for example, the uterus and placenta. In conclusion, although the absorption of drugs from the trachea and lungs is important for only a limited group of substances, pregnancy associated hyperventilation and haemodynamic changes must have an impact on pulmonary drug handling. Experimental data are lacking, and there is much room for further research.

2.3. DISTRIBUTION Once the pregnant women has absorbed a drug, it is.diluted in a greatly increased but highly variable distribution volume.

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TABLE 1. Chanoes in Blood Volume in Normal Pregnancy Non pregnant

20 weeks

30 weeks

40 weeks

2600 1400 4000

3150 1450 4600

3700 1550 5250

3850 1650 5500

Plasma volume ml Red cell volume ml Total blood volume ml

2.3.1. Plasma and Blood Volume The average increase in plasma and red cell volumes, derived from Hytten and Leitch (1971) and Pirani et al. (1973) is shown in Table 1. Plasma volume rises on average by almost 50 per cent but the individual variation is large and depends to a large extent on the size of the fetus. Thus the increase is much greater with twins and triplets (Rovinsky and Jaffin, 1965) and even greater with quadruplets (Fullerton et al., 1965); in contrast women with a poorly developing fetus will have a much smaller than average increase in plasma volume (Gibson, t973). The increase in red cell volume is relatively smaller than plasma volume, about I8 per cent (Table 1) so that there is 'dilution" of red cells leading to the characteristic fall in haemoglobin concentration. Other physiological changes, for example the fall in serum iron, the rise in iron binding capacity and the fall in ferritin levels have suggested that the fall in haemoglobin concentration may be at least partly due to iron-deficiency anaemia; but there is no significant change in the individual red cell apart from a small increase in size and a tendency to be more spherical due to the colloid osmotic changes and for most women the fall in haemoglobin to an average minimum of about 110 g per litre is purely the result Of the disparity of increase between plasma and red cell volumes (Hytten and Leitch, 1971). 2.3.2. Body Water Apart from the increase in intravascular volume there is a large increase in total body water due not only to the growth of new tissue but to a major expansion of the extracellular fluid space. An analysis of the distribution of the increased body water in pregnancy, including the blood, is given in Table 2, derived from Hytten and Leitch (1971). Again there is a very large individual variation, not so much in relation to variation in the size of the eonceptus and the increase in other tissues, but because of a highly variable accumulation of extracellular water, related to clinical oedema. Most pregnant women have visible oedema at some time during the pregnancy but clinical recognition gives little indication of the quantity of water involved. For example some 15 per cent of TABLE 2. Components of the Increased Body Water in Preonancy (g)

Fetus Placenta Amniotic Fluid Uterus Mammary Gland Blood Extravascular extracellular ('tissue') water No oedema or leg oedema Generalized oedema TOTAL with no oedema or leg oedema with generalized oedema

20

Weeks of pregnancy 30

264 153 346 264 135 538

1185 366 742 495 270 1156

2414 540 792 800 304 1083

30 500

80 1526

1680 4897

1730 2200

4294 5740

7613 10830

40

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BEATRICE KRAUER, F. KRAUER and F. E. HYTTEN

normal pregnant women are recognized as having 'generalized oedcma' (Thomson et al., 1967) although this is almost always trivial in degree and restricted to the observation of a tight wedding ring or puffy eyelids. In spite of its clinical triviality generalized oedema in normal pregnancy represents an average accumulation of 5 litres of fluid in the extracellular space, with individuals having as much as 8 litres (Hytten et al, 1966), perhaps 70 per cent of the non-pregnant volume. The widespread and variable accumulation of water appears to be in the ground substance of connective tissue, a highly active and important tissue which reacts to steroid hormones by physico-chemical changes which greatly alter its water content; it is probable that oestrogens are responsible for the uptake of large quantities of water in pregnancy (Hytten and Thomson, 1968). To what extent the enlarged body water spaces of pregnancy represent an increased area of distribution for drugs is not known but there is no reason to believe that the entire increment is not freely available. 2.3.3, Body Fat The average pregnant woman eating to appetite stores between 3 and 4 kg of body fat, largely in subcutaneous depots (Hytten and Leitch, 1971). Such a store is associated with an average weight increase of about 12 kg for the whole pregnancy and it is likely that weight gains substantially more or less than the average 12 kg will have a disproportionate effect on body fat storage. Thus a woman who in an otherwise normal pregnancy, gains only 8 kg of body weight may store little or no fat; one who gains 20 kg may well have accumulated 10 kg of fat. Fat is gained in the first two trimesters of pregnancy with little further increase in late pregnancy; indeed there is a tendency for fat to be mobilized in the last trimester of pregnancy with an increase in plasma free fatty acids (McDonald-Gibson et al., 1975). After pregnancy the accumulated fat store normally disappears within 6 months; it is unusual for women to become progressively obese with childbearing (Billewicz and Thomson, 1970). The large accumulation of fat by many pregnant women will provide a greatly increased sump for fat-soluble substances and has been used to explain, for example, the more pronounced post-anaesthetic somnolence after thiopcntone due to its slow release from this reservoir. Figure l illustrates the changes in the components of distribution volume.

ZO t8

.

g

~

.1o

t4

D2

':-

IO

"o

8

~

6

G

[~Nof ~

Plasma pregnant

tote pregnancy

Extravascular extracellular wafer

FIG. 1.

Fat

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307

2.3.4. Haemodynamic Changes Resting cardiac output rises abruptly in early pregnancy by about 1.5 litres per min and remains at that level throughout pregnancy (Hytten and Leitch, 1971); earlier findings that cardiac output declined in late pregnancy were based on measurements made with the subject lying supine, a position now known to cause a major redistribution of blood flow (see below). The increase in output is brought about by an increase in resting pulse rate of about 15 per rain and by an increased stroke volume, although the partitioning is obviously flexible since women with fixed rate cardiac pacemakers have no difficulty in adapting to pregnancy (Shouse and Acker, 1964). The increase in cardiac output is proportionately greater than the increase in oxygen consumption, particularly in early pregnancy, so that more oxygen is returned to the heart from the venous circulation and the A-V oxygen difference falls. This fact supports the suggestion above that the fall in haemoglobin concentration in the blood, 'physiological anaemia' is not abnormal; oxygen carrying capacity is clearly more than sufficient to compensate for the increased oxygen consumption and the term 'anaemia' is hardly appropriate. The distribution of the extra 1.5 litres per min of cardiac output is not fully understood but the current state of knowledge, taken from Hytten and Leitch (1971) can be summarized as follows: the uterine circulation shows a steady increase throughout pregnancy to reach a maximum at term of about 500 ml per min and renal blood flow rises early in pregnancy by about 500-600 ml per min and remains at that level throughout pregnancy; other areas of increased blood flow which cannot be quantified include a major increase in skin blood flow, an increased blood flow to the breasts and probably some increase in splanchnic blood flow. A considerable proportion of the raised cardiac output, particularly in early pregnancy, cannot yet be accounted for. The mechanism controlling the regional changes in blood flow are unknown but the situation is undoubtedly complex. Increasing blood flow to enlarging organs such as the uterus and the breasts is part of their growth and the stimulus to increased vascularity is presumably determined by local demand. The situation with peripheral blood flow is both more complicated and to some extent more important since changes in peripheral vascular tone have a profound effect on blood pressure. The overriding influence is vasodilator, well illustrated by the study of D01e~al and Figar (1965): when normal non-pregnant women are subject to a variety of 'stress' situations from having to do mental arithmetic to noise and pin pricks, peripheral vasoconstriction occurs in about 70 per cent of trials; in early pregnancy more than 60 per cent of responses are vasodilator with a gradual return to a constrictor pattern of response in later pregnancy. Several mechanisms may be involved in the tendency to vasodilation but there is at present no means of judging their importance. A number of studies, for example Schwartz and Retzke (1968) and Gant et al. (1973) have shown that the pregnant woman has a smaller pressor response than a non-pregnant woman to a given dose of angiotension, due to altered arteriolar responsiveness (Gant et al., 1974). The response may be modified as it is in the rat by progesterone (Hettiaratchi and Pickford, 1968). There is general agreement (Hytten and Leitch, 1971) that arterial blood pressure falls in pregnancy, diastolic more than systolic, reaching a minimum about mid pregnancy before returning towards non-pregnant levels at term. Posture has a major effect on the brachial blood pressure: it is highest when sitting up; lower when lying supine, with a few women showing a massive fall (the supine hypotensive syndrome); and much lower when lying in a lateral position. Venous pressure in the lower limbs rises progressively with pregnancy (McLennan, 1943) predominantly due to mechanical factors: the weight of the uterus on the pelvic veins and the hydrostatic effect of relatively high pressure blood entering the pelvic veins from the uterine circulation. The mechanical effect of uterine pressure on the pelvic veins and on the vena cava itself when the subject is supine has been fully documented by Scott and Kerr and their colleagues (Scott and Kerr, 1963; Kerr, Scott and Samuel, 1964; Lees

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et al., 1967) and Drummond et al. (1974) have shown a major effect on lower limb blood flow of the supine, compared to the lateral position. The fall in venous return from the lower limbs brought about by compression of the vena cava by the uterus, and which causes a fall in cardiac output, is reflected in a fall of about 50 per cent in central venous pressure (Colditz and Josey, 1970). Blood flow to the uterus is believed to share the diminished blood flow to the lower limbs in the supine position, particularly since compression of the aorta, as well as the vena cava, has been demonstrated (Bieniarz et al., 1968; Ohlson, 1978) but Bieniarz and his colleagues (1969) also showed that there is a low pressure drainage system for the uterus via the ovarian veins which will bypass the site of caval occlusion and may allow a preferential perfusion of the placental site. It is not possible to infer changes of uteroplacental blood flow or blood pressure, from changes in other areas, and the suggestion by Weaver et al. (1975) that epidural block in labour which increases blood flow to the lower limbs in women lying supine must divert blood flow from the uterus remains to be demonstrated. So does the widely held clinical view that exercise reduces placental blood flow. Using the technique of 133Xe clearance, Lehtovirta and Forss (1978) showed that cigarette smoking caused an acute decrease in utero-placental blood flow lasting up to 15 min suggesting a vasoconstrictor effect, possibly of nicotine. The effect of a uterine contraction on cardiovascular dynamics is uncertain, but Kerr (1976) summarized current knowledge as showing that a bolus of blood, perhaps 300-500 ml, is ejected from the uterus at the start of a contraction. This temporarily increases cardiac output and arterial pressure while reflexly slowing heart rate; since the blood is largely deoxygenated it causes a rise in the A-V oxygen difference at the heart. It has also been postulated that uterine contractions could reduce or arrest the perfusion or the intervillous space: if a drug were administered at the beginning of a contraction its access to the fetus might be impaired during the short period of high drug concentration in the maternal blood, and by the time intervillous perfusion returned to normal the concentration gradient of the drug across the placenta would be greatly reduced (Finster et al., 1966). Experimental evidence has been presented by Haram et al. (1978) to support this hypothesis: the transplacental passage of diazepam was shown to be more rapid when the high initial concentrations in the maternal circulation coincided with the relaxation period while the transfer appeared to be delayed when the intravenous injection of the drug to the mother was given during a uterine contraction. Apart from the extensive studies of the effect of lying supine, other effects of posture in pregnant women have been neglected, and the further possible effects on pharmacokinetics are unknown. Other effects in relation to placental blood flow and renal blood flow are referred to below. The effects of posture on the circulation in the non-pregnant subject have been extensively reviewed by Gauer and Thron (1965). In recumbent man more than 50 per cent of the total blood volume is contained in the systemic veins, about 30 per cent in the intrathoracic vessels and less than 20 per cent in the systemic arteries. On assumption of an upright position the intravascular pressure increases in the leg veins. With prolonged quiet standing the high filtration pressure leads to extravasation of plasma filtrate, and a concurrent decrease in blood volume may be inferred from the resulting changes in haematocrit and plasma protein concentrations. Assuming an upright position induces a large displacement of blood from the intrathoracic compartment t o the dependent parts of the body, so that the blood in the heart and the pulmonary circuit diminishes by approximately 25 per cent. This can be shown by the changes in X-ray density of the i lungs and by parallel changes in diastolic and systolic heart size. A reduction of the end-diastolic ventricular volume leads to a curtailment of stroke volume to about 50-60 per cent; and the increase in heart rate (10--20 beats per min) is not sufficient to maintain cardiac output which diminishes to 60-80 per cent of that in recumbency. If postural, blood volume displacement is avoided, as by water immersion, the fall of cardiac output can be largely prevented. The orthostatic vascular reaction is accompanied by a decrease

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of renal blood flow (Selkurt, 1963) and of hepatic blood flow (Culbertson et al., 1951), associated with an increase in renal and hepatic vascular resistance. During exercise in the erect position, the stroke volume remains just slightly below that in recumbency. This is best explained by the fact that during leg exercise the blood volume pooled in the dependent regions in the upright position is shifted into the thoracic space by muscle pump action. The role of muscle pump in the maintenance of adequate cardiac output was demonstrated in patients with congenital absence of valves in the leg veins who had a very poor working capacity in the upright position (Bevegard and Lodin, 1962). Conditions which may lower orthostatic stability are numerous, including haemorrhage, varicosities, a hot environment, general vasodilatation, psychic stress and prolonged bed rest causing a gradual deterioration of cardiovascular function. A few clinical studies on the effect of posture on the pharmacokinetics of drugs have been performed: for example, it has been shown that during recumbency the elimination rates of some drugs which are predominantly excreted by renal mechanisms is increased (Dettli and Spring, 1966; Levy, 1967; Krauer, 1969). The clearance of drugs which are eliminated by liver metabolism with a high extraction ratio may also be influenced, since their clearance rate is dependent on liver blood flow (ElfstrSm and Lindgren, 1978; Wilkinson, 1975). 2.4. METABOLISM

Pregnancy is characterized by major changes in almost every aspect of metabolism: for example, the body temperature is raised by about 0.5°C during the first half of pregnancy (Buxton and Atkinson, 1948) by a resetting of the central control set point (Cunningham and Cabanac, 1971); levels of free thyroxine (T4) are probably somewhat below non-pregnant levels (Finucane et al., 1976; Avruskin et al., 1976) so that all maternal tissue may be metabolizing at a somewhat reduced tempo; and the metabolism of all nutrients is conspicuously altered (Hytten, 1978). Although there is little evidence of changes in drug metabolism in pregnancy, it would be surprising if they escaped the general rearrangements. 2.4.1. T h e Liver The liver plays a key role in many aspects of metabolism, including drugs, but remarkably little is known of any changes which occur in pregnancy. According to Combes et al. (1963) the human liver is not enlarged in pregnancy as it is so conspicuously in such laboratory animals as the rat. And although there is some dispute about changes in liver blood flow (Tindall, .1975) the one study where blood flow was measured directly by the Fick principle (Munnell and Taylor, 1947) found no difference between pregnant and non-pregnant women. Nor have any specific histological changes been observed although minor, wholly non-specific differences have sometimes been seen in biopsies from normal pregnant women (Nixon et ai., 1947; Dietel, 1947). They include variation in cell size, irregularity of nuclei and occasionally increased fat and glycogen accumulation. Cholestasis, characterized by increased bile viscosity and histologically dilated bile canaliculi is probably common in pregnancy, particularly it seems in Scandinavia (Aldercreutz et al., 1967; Layden et al., 1975), but it is seldom clinically apparent with only a few women developing the characteristically itchy skin and even fewer clinical jaundice. The condition is totally reversible and is probably an effect of oestrogen, women taking oral contraceptives developing a similar picture (Song et al., 1969). One major function of the liver, phagocytosis, is greatly enhanced by pregnancy in experimental animals including monkeys (Wexler and Kantor, 1966) by proliferation of the Kupffer cells under the stimulus of oestrogen; there may be a similar effect in human pregnancy but direct evidence is lacking.

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Of liver function tests, the most studied has been the clearance of the injected dyes bromsulphthalein (sulphobromophthalein; BSP), or indocyanin green, which in the normal person are rapidly removed from the blood by the liver, conjugated and excreted in the bile. There is general agreement that the level in the blood of injected dye falls more slowly than usual during pregnancy (Tindall, 1975; Rudolf et al., 1977). Tindall and Beazley (1965) presented detailed evidence indicating that the removal of BSP from the blood was a little more rapid than usual but that the rate of return of the dye from the liver to the blood was almost double the non-pregnant rate, because, they suggested, of delayed excretion from liver to bile or competition by oestrogen for binding sites in the liver cell. Crawford and Hooi (1968) considered the difference to be due entirely to the greatly increased avidity of binding by plasma proteins holding the BSP in the blood. Combes et al. (1963) found the storage capacity of the liver for BSP to be increased by about 22 per cent but the maximum excretion rate (Tm) of BSP into the bile fell by 27 per cent. The increased binding of BSP to blood proteins and the impaired excretory capacity from liver cell to bile canaliculi was reproduced by oestrogen administration to nonpregnant subjects (Mueller and Kappas, 1964). That would explain the picture in pregnancy and the observation by Beazley and Tindall (1966) that the phenomenon was exaggerated in multiple pregnancy. The relevance of these and other possible changes to hepatic drug elimination are not well characterized. For example cholestasis prolongs the half-life of some drugs (Harrison and Gibaldi, 1976) and could impair the elimination of drugs such as rifampicin (Krauer and Krauer, 1977). Changes in liver enzyme activity are also likely but little understood. An increased capacity for hydroxylation is presumably induced by the rising tide of sex steroids in the maternal blood, but in normal pregnancy this must fall far short of exceeding the liver's capacity to produce enzyme because the much greater increase associated with multiple pregnancy does not overwhelm it. Draffan et al. (1976) assumed such induction to explain the somewhat reduced half-life of amobarbital but metabolism was not increased by prolonged administration of the drug itself or phenobarbital. On the other hand the sex steroids have been shown to be competitive inhibitors of microsomal oxidases for drugs such as ethylmorphine or hexobarbitone and may therefore reduce their elimination rate (Davis et al., 1973). Morrison et al. (1976) could find no change in maternal pethidine metabolism but there is a report by Glenc (1972) claiming increased acetylation of sulphonamides. Because of the relatively slow time course of enzyme induction, the sudden withdrawal of the sex steroid substrate after delivery might leave a greatly increased capacity to dispose of drugs. There is no evidence that this theoretical possibility has an important effect and in at least one instance where drug levels have been shown to fall precipitously after delivery--that of ph~nytoin (Landon and Kirkley, 1979) metabolism was not the explanation because there was no corresponding increase in the production of the metabolite. It seems more likely that the phenomenon is one of malabsorption of the drug in labour, perhaps due to the taking of antacids (see p. 302). If drug metabolism should be impaired for any reason then the effects may be serious for the fetus. For example the 'fetal alcohol syndrome' where both physical and mental development of the fetus are grossly deranged does not occur in all infants born to alcoholic mothers; V6ghelyi et al. (1978) have presented evidence that its occurrence is due not to alcohol but to high levels of acetaldehyde in mothers who have developed an impaired capacity to degrade it. A pregnant alcoholic taking disulphiram would similarly put her fetus at risk if she were to consume any alcohol. 2.4.2. T h e Feto-Placental Unit In addition to its contribution to the increased distribution volume for drugs the feto-placental unit can also contribute to drug metabolism.

Drug disposition and pharmacokinetics

311

2.4.2.1. Placental drug metabolism. The placenta seems to contain the metabolizing enzyme systems for each of the classical reaction types: oxidation, reduction, hydrolysis and conjugation, and many substances, both endogenous and exogenous, undergo biotransformation in human placental tissue. Yet only very little quantitative information is available: hydroxylation of benzo (~) pyrene has been identified by several authors and it seems that cigarette smoking induces the reaction during the later, but not during the early stages of pregnancy (Juchau, 1976; Schlede and Scholz, 1974; Nebert et al., 1969; Welch et al., 1968). Reduction systems have been identified in human placental tissue for azo-linkage and nitro-group reduction (Juchau et al., 1968; 1973; Juchau, 1969). Hydrolysis in human placental fractions was reported for meperidine (Van Petten et al., 1968) and for acetylsalicylic acid and procaine (Juchau and Yaffe, 1969), and conjugation reactions including acetylation and conjugation of glycine with PABA have also been described by these authors. The placenta also contains enzymes capable of metabolizing pharmacologically active endogenous compounds: vasoactive substances such as epinephrine, norepinephrine, serotonin, histamine and acetylcholine and polypeptide hormones such as insulin, oxytocin, angiotensin, and vasopressin, some of which are used in therapeutics and may therefore be referred to as drugs (Juchau, 1976). Naturally, drug biotransformation does not necessarily mean that the parent drug becomes inactivated. On the contrary, in some cases the pharmacological effect occurs as a result of the formation of an active metabolite. Thus, the placenta could theoretically convert inactive drugs to active (teratogenic, mutagenic or carcinogenic) metabolites. On the other hand primarily toxic substances may become less accessible to the fetus and/or lose their toxicity through placental biotransformation. 2.4.2.2. Fetal drug metabolism. There is considerable evidence that human fetal tissue is able to perform a number of metabolic functions and extensive monographs and reviews on this subject have been published (Rane, 1973; Saarikoski, 1974; Sereni et al., 1973; Yaffe and Juchau, 1974; Pelkonen et al., 1975; Dutton, 1978). Because the fetal compartment is so small compared to the maternal, drug excretion or metabolism by the human fetus has usually no discernible effect on maternal drug concentrations, but the fetal:maternal drug concentration ratio could thereby be decreased. Drug metabolites are distributed between mother and fetus according to their lipid solubility and degree of ionization. Usually, the parent drug is metabolized to more polar compounds which do not cross the placental membrane so easily. On the maternal side these compounds will be eliminated, mostly by renal mechanisms. On the fetal side the highly polar metabolites may accumulate. Some such compounds may be pharmacologically active e.g. diazepam metabolites (Cree et al., 1973). Moreover, there is the possibility that toxic reactive intermediates may be formed within the fetus; drugs like carbamazepine, secobarbital, phenytoin (diphenylhydantoin), phenobarbital, cyproheptadine, opipramol yield epoxide metabolites which are believed to be related to some teratogenic effects (Rane and Gustafsson, 1973; Piafski and Rane, 1978; Ames et al., 1972). Model 1 (Fig. 2A-D) illustrates different possibilities of drug and drug metabolite transfer between mother and fetus after administration of a parent drug to the mother.

2.4.3. The Blood Little metabolism takes place in the blood itself but pseudocholinesterase is active and is unusual among plasma enzymes in that its concentration falls during pregnancy in about 30 per cent of women (Shnider, 1965). In some women that fall may be so great that they have an impaired ability to hydrolyse the muscle relaxant succinylcholine and may suffer undesirably profound and prolonged action after its administration in the usual anaesthetic doses.

312

BEATRICE KRAUER,F. KRAUERand F. E. HYTTEN

A

Mother

[

Placenta

Fetus

m

Parent drug (nan polar)

Parent drug (nan polar)

Polar metab.

I!

1

Elimination

Mother

l

Placenta

Parent drug (non polar)

V-1

l

Nan polar metab. Polar meta~

--

-

" I

,J

Fetus .

I

Parent drug ( non polar)

l

Nan polar metab.

1,

Elimination

C

Mother

1

Placenta

R

Parent drug ( non ipolor )

Parent drug (non polar )

1

t

Non polar mefab.

Non polar metab. Palar metob.

I

I

J m

Elimination

D

Mother

1 Parent drug (polar)

Fetus

~ Polar Letab. i f

Elimination

Placenta_

Fetus

No drug

Elimination F]G. 2. (A) The parent drug is non polar and easily crosses the placenta to reach the fetus. Polar metabolites are formed in the mother, but do not cross the placenta and are eliminated by maternal renal excretion. (B) Non polar metabolites are formed in the mother and cross the placenta easily in both directions. Further metabolism to polar metabolites and subsequent elimination occur only in the mother. (C) The non polar parent drug and non polar metabolites equilibrate across the placenta between mother and fetus. Polar metabolites formed on either side of the placental membrane do not cross the placenta. They are eliminated by the mother, but may accumulate on the fetal side. (D) The parent drug which is administered to the mother is so polar that it does not cross the placenta but is eliminated unchanged by maternal renal excretion.

Drug disposition and pharmacokinetics

313

2.5. PROTEIN BINDING

Most drugs are partly bound to the plasma proteins, predominantly albumin. Usually, the binding is reversible and the number of binding sites is limited, so that the binding equilibrium is adequately described by the law of mass action and the system may become saturated, reaching its maximum when all binding sites are occupied (Dettli, 1974). A great number of endogenous and exogenous (drug) molecules seem to be bound to the same protein molecules. This lack of specifity combined with the saturable nature of the binding process constitutes the basis for possible interactions: when two substances compete for the same binding sites the probability that one substance will displace the other will increase with its binding affinity and its concentration. Thus, an increasing competition for binding sites by non-esterified fatty acids (Spector et al., 1973) which show a significant increase in plasma concentration during the last trimester (McDonald-Gibson et al., 1975) could be in part responsible for the observed decrease of salicylate binding in plasma obtained from pregnant women (Krasner and Yaffe, 1975). It has been shown that there are substantial differences in the plasma protein binding of many drugs, due to genetics (Wilding et al., 1970), environmental factors (Sellers and Koch-Weser, 1970), pathological states (Anton, 1968; Jusko, 1976) and age (Wallace et al., 1976). There are conflicting reports with respect to the relative binding of drugs to human fetal and maternal plasma, or that of healthy adults: Ehrnebo et al. (1971) found little binding capacity of fetal plasma for ampicillin, benzylpenicillin, phenobarbital and diphenylhydantoin. Tucker et al. (1970) found bupivacaine and lignocaine to be less extensively bound to fetal than to maternal proteins at the same concentration ranges. By contrast, other compounds, like thiopental, seem to bind equally to either fetal or maternal plasma (Finster et al., 1966). No differences in protein binding between maternal and fetal plasma have been reported for methicillin and dicloxacillin (Depp et al., 1970) and the same binding capacity for sulphaphenazole was measured in fetal and in adult plasma after removal of bound endogenous ions (Chignell et al., 1971). The binding of diazepam to newborn and adult serum is similar (Krasner and Yaffe, 1975). Finally, the protein binding of salicylate has been reported to be more extensive in umbilical cord plasma than in the plasma of pregnant women close to term or at term (Crawford and Hooi, 1968). Similar results were obtained by Levy et al. (1975) who found a neonatal:maternal salicylate concentration ratio of 1.6 and explained this by the more extensive plasma protein binding of salicylate in the fetus than in the mother near term. The concentration of plasma albumin falls in the first half of pregnancy by between 5 and 10 g per litre, from 35 to between 25 and 30 g per litre (Hytten and Leitch, 1971). While this must reduce the binding capacity of a given volume of plasma it should be remembered that the rise in plasma volume (see p. 305) ensures that the total mass of albumin in the circulation is at least as great in late pregnancy as before pregnancy (Fig. 3). For highly bound drugs the hypoalbuminaemia of pregnancy will produce a lower total plasma concentration associated with a decrease of the bound drug fraction and a corresponding increase of the free drug fraction in the plasma. But in turn this may result in a greater distribution in the extravascular compartments and/or in an increased metabolism and excretion, proportional to the free drug fraction in the plasma (Levy and Yacobi, 1974; Gibaldi and McNamara, 1978), so that the absolute free drug fraction in the plasma may remain unchanged. While albumin concentration in maternal plasma falls, albumin produced by the fetus, which does not cross the placenta, increases gradually in the fetal plasma. This results in progressively higher values of the fetal:maternal plasma albumin concentration ratio (Studd et al., 1970). Consequently, depending on the stage of gestation, it is possible to find fetal:maternal plasma albumin concentration ratios lower, equal or higher than unity. It is generally accepted that the pharmacological ac-tivity of-a-dr-ug i-s related-to the concentration of its unbound molecules, i.e. the fraction of free drug in the plasma. The

314

BEATRICE KRAUER, F. KRAUERand F. E. HYTTEN Plasma albumin in pregnancy

I00

Cn

2 P-

90

80

70

I 0

I tO

I 20

Weeks

I 30

I 40

of pregnancy

FIG. 3.

degree of binding in the individual patient will therefore be important for the interpretation of the plasma level of usually highly bound drugs (Gugler and Azarnoff, 1976). Thus, a higher incidence of side effects may be predicted if hypoalbuminaemic patients have increased plasma concentrations of free drug. Accordingly Greenblatt and Koch-Weser (1974) found an increasing proportion of adverse reactions to diazepam related to falling albumin levels (within the range found in pregnancy), due to a rising fraction of unbound drug. Similarly, if a drug is administered to a pregnant woman in early gestation, the albumin concentration in the fetal plasma being considerably lower and the fraction of free drug molecules accordingly higher than in the maternal plasma, the possibility of toxic drug effects for the fetus may ensue, even at lower than normal plasma drug concentrations. In contrast to albumin, most globulin fractions rise in pregnancy (Studd, 1975) with particular increases in a number of carrier proteins which bind specific substances, such as transferrin, the sex steroid binding proteins and thyroxine binding globulin. The role of these protein changes in pregnancy has not been quantified, but both diazepam and phenytoin for example, are known to compete for binding sites on thyroxine binding globulin (Schussler, 1971; Wolff et al., 1961). The total effect of the changing patterns of plasma proteins and of physiological competitors for their binding sites is complex and will almost certainly vary from drug to drug; there is much room for research.

2.6. EXCRETION 2.6.1. The Kidney Of all the physiological systems which are modified by pregnancy, renal function perhaps undergoes the greatest change and for reasons which are far from self evident; they make little biological sense. Renal plasma flow almost doubles, in the study by Dunlop (1976) from 444 ml p-r min, to 836 ml per min in late pregnancy. The earlier study by Sims and Krantz (1958) found a somewhat smaller rise, from about 450 ml to about 730 ml per min but showed that it w a s present from at least 15 weeks of pregnancy. Glomerular filtration rate behaves

Drug disposition and pharmacokinetics

315

similarly with an increase from about 100ml per min to 170ml per min occurring in early pregnancy and continuing until term (Davison and Hytten, 1974). It seems likely that the increase occurs rapidly in the first few weeks of pregnancy (Davison, unpublished). Both renal plasma flow and glomerular filtration rate may be susceptible to changes of posture although the major effect of the supine position in depressing renal plasma flow found by Chesley and Sloan (1964) could not be duplicated by Dunlop (1976). The fact that endogenous creatinine clearance over 24 hrs showed a fall in late pregnancy when clearance measured by infusion in the sitting position did not, suggested to Davison and Hytten (1974) that intermittent postural effects during the course of 24 hrs may have made the difference. There is a more obvious postural effect on urine flow which is depressed when the woman in late pregnancy lies on her back (Walker et al., 1934; Prichard et al., 1955). The effect may be due to the curious and unexplained phenomenon, demonstrated by Lindheimer and Weston (1969) of active reabsorption of sodium by the proximal tubule in the supine position. Diurnal variation of sodium excretion is probably a postural effect of a different kind. The normal non-pregnant person has a considerably reduced electrolyte and water excretion during the night, a rhythm which is not easy to disturb and which is not merely a reflection of fluid intake. In pregnant women who are ambulant the pattern is reversed (Vedra and Horskh, 1964), though not in pregnant women confined to bed in hospital (Pystynen and Pankamaa, 1965). The reversed pattern is almost certainly due to the sequestration of water in the tissue spaces of the lower limbs due to the high venous pressure and the low colloid osmotic pressure of the plasma. When the woman goes to bed and the effect of gravity is removed, venous pressure falls, and 'the equivalent of an infusion of isotonic saline is delivered to the vascular compartment' (Sims, 1968) leading to increased excretion of salt and water and the characteristic annoyance of nocturia. The effect of the raised glomerular filtration rate on drug elimination will depend on the concentration of free drug in the plasma which will in turn depend on the complex interplay of factors which determine binding to plasma proteins. Indeed the amount which appears in the urine may give a good indication of effective drug levels. It is likely that the huge increase in filtration will have a major effect on the excretion of at least those drugs excreted unchanged in the urine. More information is needed. In the common complication of pregnancy, pre-eclampsia, proteinuria may be a feature. This will not only result in reduced plasma albumin levels and hence affect drug binding, but there may be substantial loss of bound drug in the urine.

2.6.2. The Liver Some drug excretion will occur via the bile and will also be affected by protein binding. There is almost no information about the effect of pregnancy on this route of drug elimination.

2.6.3. The Lungs When the intake of a substance by inhalation is stopped pulmonary elimination begins. The factors affecting de-equilibration are the same as those involved in equilibration (see 2.2.3.). A compound of very low lipid-solubility can be eliminated almost as rapidly as the blood delivers it to the lungs. The elimination of an agent of very high lipidsolubility is limited by the respiratory rate and respiratory minute volume. Thus, the curves of de-equilibration are essentially inverted equilibration curves (Goldstein et al., 1974). J.P.T,

10/2--J

316

BEATRICE KRAUER, F. KRAUERand F. E. HYTTEN

3. FETAL D R U G EXPOSURE The so called 'placental barrier' which separates the maternal from the fetal compartment must be regarded as an epithelial membrane of lipoid character; i.e. a lipid sieve which lipophilic non-polar substances are able to penetrate according to their concentration gradient and degree of lipophility. Since drugs are usually weak acids or bases they will display in their neutral form some degree of lipophilism and their move across the epithelial membrane will ensue in accordance with non-ionic distribution: a difference in pH on either side of the membrane will be followed by an accumulation of the bases in the more acidic space and of the acids in the more basic space. On the other hand it has also been shown that polar molecules can permeate the membrane, although to a limited extent, through small water pores (Kurz and Fasching, 1968). The rate of this diffusion does, not depend on the total concentration of the substance, but on the concentration of free molecules dissolved in the plasma water: the greater the extent to which the molecules are bound to plasma proteins the slower will they permeate the membrane. The passage of polar molecules is thus the result of a restricted diffusion and is therefore extremely slow. Apart from these major mechanisms such factors as pinocytosis, phagocytosis, active transport and disruption can alsobe involved in placental drug transmission, albeit to a minor extent. Since any substance administered to the mother in sufficient quantity will eventually reach the fetus (Villee, 1965; Horning et al., 1973; Ginsburg, 1971) the question arises: how much and at what rate does the drug enter the fetal circulation and how long does it remain in the fetus? Depending on the mechanisms of drug action it will be important to ascertain either the time course of drug concentration in the fetus--for reversibly acting drugs like antidepressants (Levy and Gibaldi, 1972), or the total drug level-time integral--for irreversibly acting drugs like dysmorphogens (Levy and Hayton, 1973). It has been suggested that an index of relat~,ve exposure of the fetus to the drug taken by the mother can be calculated from the ratio of the total area under the drug concentration-time curve for the fetus to that of the mother from the time of drug administration to the time when all drug has been eliminated. For practical purposes, it may be postulated that drugs which are intended to reach the fetus should have a high index, while drugs which should preferably not reach the fetus, but which are destined for the mother should have a low index of relative exposure to the fetus. Fetal exposure to a drug depends on various processes: the rate of drug intake by the mother, the rate of drug elimination by the mother, the drug transfer rate across the placenta in both directions (maternal-fetal and fetal-maternal), the drug distribution rates in mother and fetus and the drug elimination rate by the fetus itself. In addition, specific factors like metabolism by placental tissues, first-pass effects and recycling phenomena may be involved (Levy, 1975). Measuring drug concentrations in the human fetus is in most cases not possible, but if one considers the placental membrane as an uninterrupted membrane of epithelial type separating the maternal from the fetal organism the problem of fetal exposure may be approached by analysing the drug concentration--after complete absorption of the dose--in the maternal plasma and urine simultaneously. This allows an estimate of the dose fraction eliminated unchanged in the urine fr and the fraction of the dose eliminated by extrarenal mechanisms f,r = 1 - ft. When the overall elimination rate constant k~ in the plasma and the renal elimination rate constant k, in the urine is determined, one can calculate the extrarenal elimination rate constant k,r = k~ - kr. The fraction of the dose eliminated unchanged in the urine f~ = k~/k~, and the fraction eliminated by extrarenal mechanisms f,r = k,Jk~. After introducing the expression Q which describes the drug elimination rate as a fraction of the normal elimination rate constant kN (Dettli, 1977)

Q-

ke k,r kr kN-- kN + k-~

Drug disposition and pharmacokinetics

317

the expression knr/kN may be defined as Qo. Qo represents the fraction of the absorbed dose eliminated by extrarenal mechanisms in individuals with normal kidney function N. Under normal conditions ke = ks; hence Q = 1 and k,dkN = fnr- It thus becomes clear that for a drug which is normally entirely eliminated unchanged by the kidneys Qo = 0; and for a drug whose elimination is not dependent on the kidney function Qo = 1. Insofar as the placental membrane is regarded as a continuous epithelial membrane (which is certainly the case at least during early pregnancy) the determination of Qo is an important factor when estimating thedose fraction which may eventually reach the fetus: the more Qo ~ 1 the less unchanged drug will be able to reach the fetus, and conversely the more Q0 ~ 0 the more unchanged molecules will be able to permeate the membrane. Obviously, far more comprehensive pharmacokinetic models which would allow us to predict drug concentration-time curves on the basis of experimentally determined rate and volume constants in the fetus are technically and ethically so difficult to obtain that one has to fall back on occasional descriptions of fetal drug concentrations, usually at therapeutic abortion, or at delivery or shortly before, when using the technique of fetal scalp blood sampling during labour. The classical study consists in the administration of a drug to the mother shortly before delivery and the determination of the drug concentrations in the maternal and the cord blood at the time of delivery. Increasing amounts of such data are being published, but the pharmacokinetic characterization of the fetalplacental-maternal unit involving studies on placental transfer and fetal drug exposure remains extremely difficult and must be based on a composite of data from different subjects, at different times and under different conditions. In order to maximize information gained from studies which yield only single point determinations of drug concentrations in the fetus, pharmacokinetic models have been constructed in which the time course of drug concentration is mimicked under various conditions in mother and fetus by computer simulation. 3.1. THE PHARMACOKINETICAPPROACH

In recent years increasing interest in pharmacokinetics has led to the development of sophisticated techniques allowing refined descriptions of pharmacokinetic processes on the basis of multi-compartment models. However, it is evident that any pharmacokinetic model remains a simplification of the real biological system, and the development of more complicated models only provides marginally closer approximation to reality. Besides the experimental difficulties, such as sampling or assay problems which limit the precision of the obtainable data, it can be extremely difficult to distinguish between a two---or more--compartment system on the basis of plasma concentrations alone (Levy et al., 1969). For the practical purpose of predicting drug time concentration courses in patients it therefore becomes questionable whether the choice of simpler models is not more suitable (Hermans et al., 1975). The complexities can then be largely avoided, by restricting the kinetic analysis to the period of exponential drug decline. However, significant underestimates of the drug's half-life may be obtained when a two-compartment model is interpreted in terms of a single-compartment model, or when a multi-compartment system is treated as a two-compartment system. An estimation of the drug's half-life during the steady state can prevent such errors (Gibaldi and Weintraub, 1971). Depending on the drug and the available experimental data, the body may be represented as a one- or more-compartment system. When a drug is assumed to be absorbed and distributed immediately the organism can be considered to be acting like a single compartment with respect to this particular drug. Drug absorption and distribution requires a finite period of time which results in a lower and more delayed peak of drug concentration in the plasma than the dose would theoretically yield if the drug had been absorbed and distributed instantaneously. The difference between theory and reality depends on the relation between the absorption rate constant ka and the elimination rate constant ke (Dettli, 1977).

318

BEATRICEKRAUER.F. KRAUERand F. E. HYTTEN

When the overall elimination rate constant k e of the drug is not by far the slowest drug transport process the pharmacokinetic characterization has to be based on a twocompartment model which consists of a central, rapidly accessible, 'fast' or 'shallow' compartment and a peripheral, slowly accessible, 'slow' or 'deep' compartment. The drug will initially not only be eliminated, but will penetrate simultaneously into the peripheral deep compartment, with the rate constant k12, until the drug concentration becomes equal in both compartments. At this moment the peak concentration in the deep compartment is reached. The slower the exchange rate with the deep compartment the more delayed the achievement of the peak concentration in the deep compartment and the lower the level of this peak. Because the elimination process continues, the drug concentration thereafter becomes lower in the central than in the peripheral compartment. Consequently, drug molecules will diffuse back from the peripheral into the central compartment with the rate constant k21. This back diffusion of drug molecules will slow the rate of fall of plasma drug concentration until a constant value is reached towards the end of the elimination process. The time period during which this constant slope is maintained is usually referred to as the//-phase (~ being the terminal slope of exponential drug disappearance from the plasma in a two-compartment open model system). Sometimes, the penetration of a drug into a peripheral compartment is so slow that the fl-phase is only found after a considerable time. The plasma drug levels may then be so low that precise determinations are impossible after a single dose and the half-life must be estimated after several doses from a steady state study (Gibaldi and Weintraub, 1971). The term distribution may have different meanings: the progressive process of distribution; and the state of spatial distribution of the drug within the body after reaching diffusion equilibrium (Dettli and Spring, 1973). The concept of the distribution volume V was primarily developed as a mathematical constant relating the amount of drug in the body with the concentration in the plasma c. In order to evaluate V different methods have been used: constant rate intravenous infusion or instantaneous intravenous injection, the latter creating the situation of the so-called fl-phase pseudo-distribution equilibrium. At equivalent plasma concentration larger tissue :central compartment distribution ratios are obtained during the fl-phase pseudo-distribution equilibrium some time after instantaneous intravenous injection than during constant rate intravenous infusion equilibrium. The difference between the drug distribution ratios at pseudo-distribution equilibrium and at ongoing infusion equilibrium depends on the relative magnitudes of k2~ and fl and varies from one drug to another (Gibaldi, 1969). The different findings reflect entirely different pharmacokinetic situations.

3.2. COMPARTMENTAL CHARACTERIZATION OF THE FETO-MATERNAL UNIT One way of obtaining a better understanding of the pharmacokinetic processes in the feto-maternal unit is to mimic the time course of drug concentrations by means of computer simulation, where mother and fetus function as one- or more-compartment systems with fast or slow pharmacokinetic characteristics. The resulting curves are then compared to the data on various drug concentrations available from the literature (Levy and Hayton, 1973). Model 2 (Fig. 4) illustrates schematically the drug transfer and elimination process (metabolic and excretory) by the mother, the placenta and the fetus. The simplest model consists of mother and fetus, each represented by a single fast compartment. In this case, the drug equilibrium and a fetal ~maternal concentration ratio of about unity is attained quickly, as well after rapid intravenous injection as during a constant intravenous infusion. This type of distribution fits the data found for thiopentone (Moya and Thorndike, 1962). If the drug enters the fetal compartment slowly, while its elimination continues from the maternal compartment, the concentration in the fetal plasma will eventually become higher than in the maternal plasma. Accordingly, the fetal:maternal drug concentration ratio will be lower during than after an infusion or after a rapid intravenous injection.

Drug disposition and pharmacokinetics

319

l ko k4~ Mc

c2 v~ I k2'

Ct

Vl

I,.M

keF

FiG. 4. The mother M is represented by a central (M,.) and a peripheral (Mo) compartment; P is the placental, F is the fetal compartment; k, is the rate constant of drug absorption, k,M, k~p, k~F are first order rate constant of drug elimination (including metabolism and/or other excretion) for the mother (M), the placenta (P) and the fetus (F), respectively, kt2 and k2t are the .transfer rate constants between maternal central and peripheral compartments, k~3 and k31 are the transfer rate constants between central maternal and placental compartments, k34 and k43 are the transfer rate constants between placental and fetal compartments, k41 is the transfer rate constant between fetal and maternal central compartments. The amount of drug in the body is given by the concentration of drug C times the apparent volume of distribution V. V~, V2. V 3, V4 are the apparent volumes of distribution; C,, C2, C3, C4 are the drug concentrations in the different compartments.

This type of distribution has been found for salicylates (Levy and Garrettson, 1974; Levy et al., 1975; N6schel et al., 1972) and diazepam (Id[inp~i~in-Heikkila et al., 1971; Mandelli et al., 1975). A more complicated model may represent the mother as a two-c0mpartment system with a central compartment corresponding to the plasma and the site of drug elimination and an additional peripheral tissue compartment. If the maternal tissue is slowly accessible, while the fetus is rapidly accessible, the simulated drug concentration course will be almost identical in the fetal compartment and in the central maternal compartment during and after infusion. This type of drug distribution fits the data recorded for tetracyclines (Le Blanc and Perry, 1967). If the fetus is slowly accessible and the maternal tissue is more rapidly accessible than previously, the fetal:maternal concentration ratio will be higher than unity in the postdistribution phase, with a marked maximum some time after injection or infusion. This is the case for ampicillin (Perry and Le Blanc, 1967) and meperidine (Beckett and Taylor, 1967; Morgan et al., 1978). The amniotic fluid can be regarded as an additional compartment to the fetal-maternal unit. The volume of the amniotic fluid is extremely variable, but it reaches a maximum of around one litre at about 36 weeks and declines slowly thereafter. Up until about 20 weeks of pregnancy the volume of amniotic fluid is closely related to fetal weight, it has the same characteristics as fetal extracellular fluid, and is almost certainly a continuation of it through the permeable fetal skin.. After 20 weeks the fetal skin keratinizes and amniotic fluid becomes an externalized fluid in which not even such diffusible substances as sodium and urea equilibrate with fetal or maternal extracellular fluid; it represents a balance between fetal urine production and fetal swallowing (Lind and Hytten, 1972). If there are other avenues of exchange these must be unimportant because absence of fetal kidneys leads to a virtual absence of amniotic fluid and inability of the fetus to swallow leads to hydramnios. The fetus is immersed in amniotic fluid in which many drugs and drug metabolites have been identified (Amon and Amon, 1976; Hirsch et al., 1974; Prakash et al., 1970; Sommer et al., 1975; Duignan et al., 1973). Routes of access for drugs to the amniotic fluid have not been defined and while it is likely that the major avenue is the fetal urine, direct transfer across the amnion and chorion, and across fetal skin and exposed mucous surfaces may be possible.

320

BEATRICEKRAUER,F. KRAUERand F. E. HYTTEN

If access to amniotic fluid of a drug depends predominantly on its transfer to, and excretion by, the fetus, a considerable delay after administration to the mother would be expected for drugs which reach the fetus slowly; and that has been observed in early pregnancy for meperidine (Szeto et al., 1978) and in late pregnancy for ampicillin (Bray et al., 1966). If drugs accumulate in the amniotic fluid compartment, the latter may become a slowly equilibrating reservoir with the characteristics of a deep compartment (Mirkin and Singh, 1976). This could be of practical importance, when therapeutic drug concentrations are to be maintained over a prolonged period in the amniotic fluid. 3.3. FACTORSWHICH MAY INFLUENCEFETAL EXPOSURE Fetal:maternal drug concentration ratios different from unity depend greatly on the apparent volumes of distribution and depths of the different compartments involved. Other factors may also be important, such as differences in protein binding, in acid-base equilibrium, in the metabolic and excretory functions of the placenta and the fetus itself, and in haemodynamics. Some of these aspects have already been discussed: distribution volumes (p. 304-306; p. 318); haemodynamics (p. 308) and protein binding (p. 313-314). 3.3.1. The Effect of Acid-Base Equilibrium According to the theory of non-ionic partitioning uncharged molecules with high lipid solubility permeate the cell membrane more quickly than the less lipid soluble ionized molecules. The transfer of weakly acidic or basic drugs across the placenta will therefore be influenced by the respective pH of the maternal and the fetal fluids, particularly when the drugs possess pK a values close to the pH of the environmental fluid. The fetal plasma is usually about 0.1 pH units lower than the maternal plasma. For weak bases this pH-difference results in a higher concentration of undissociated molecules in the maternal than in the fetal circulation and hence in a net transfer of basic drug molecules from the maternal to the fetal compartment. As a consequence fetal drug concentration may exceed that of the mother at equilibrium (Asling and Way, 1972; Lima et al., 1978). The same is true for the situation in the amniotic fluid. The pH of the amniotic fluid being lower than that of the maternal plasma (Seeds and Hellegers, 1968), the accumulation of weakly basic drugs such as meperidine will be facilitated by ion-trapping, because the pH-gradient will favor the ionization of the basic drug in the more acidic amniotic fluid and therefore only a small fraction of unionized drug molecules would be able to diffuse directly back into the maternal compartment. 3.3.2. Drug Biotransformation in the Feto-Placental Unit Generally, drug biotransformation depends on the reversible binding of drug molecules to a limited number of enzyme molecules. Saturation phenomena occur, depending on the relation of the dissociation constant K of the drug-enzyme complex (which characterizes the affinity of the drug molecules to the enzyme molecules) and the drug concentration in the plasma c. At low drug concentration ranges, when c <~ K, the metabolic rate k will follow apparent first order kinetics, increasing in proportion to the drug concentration in the plasma c, where k = -(dc/dt)/c. With increasing values of c the metabolic rate k will not increase proportionately any more to c, but approaches a constant maximum value v max, where following a zero-order process k = -dc/dt. The deviation from first order kinetics can be adequately described by Michael-Menten kinetics or dose-dependent, capacity-limited saturation kinetics (Levy, 1968; Gerber and Wagner, 1972; Wagner, 1973; 1978). For some drugs saturation phenomena occur at low. therapeutic concentration ranges. As a consequence very high steady-state levels are reached after repeated administration.

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In the feto-placental unit, depending on the pharmacological activity of the drug and its metabolites, this may have important implications: saturable drug kinetics in the placenta may lead to toxic drug concentrations and deleterious effects for the fetus. On the other hand--if fetal metabolism yields toxic metabolites--saturation kinetics may protect the fetus from rising levels of toxic components. A remarkable phenomenon in drug biotransformation is the possibility of enzyme induction provoked by the pre- or coadministration of an inducing agent (Conney, 1967). In kinetic terms this means an increase in the number of enzymatic binding sites, and consequently an increase of v max. But enzyme induction does not necessarily result in a dramatically increased rate of metabolism, because when only a small percentage of the drug's total metabolism occurs over the pathway that has been induced, the overall effect of metabolic induction will be negligible. Moreover, when a drug has a high extraction ratio; i.e. when it is metabolized to a great extent during one passage of a particular organ (first-pass metabolism), the rate of metabolism becomes flow-limited, and even a marked increase of v max by enzyme stimulation will not increase the metabolic rate if that organ's blood flow is not simultaneously enhanced (Shand, 1976; Wilkinson, 1975; Dettli, 1974). There is also the possibility that the rate-limiting step in biotransformation is not the amount of enzyme present, but the availability of a conjugation substrate. If this substance is not added simultaneously the metabolic transformation rate will not increase (Levy and Amsel, 1966). Some such conditions may certainly be encountered in the feto-placental unit, but although there is ample evidence of fetal and placental metabolic activity the final assessment of quantitative data throughout pregnancy which would allow more precise pharmacokinetic predictions on drug and drug metabolite behaviour in the feto-placental unit are lacking. 4. THE USE OF DRUGS D U R I N G PREGNANCY In the past, most investigations on drug intake during pregnancy were conducted in retrospect--usually in an attempt to identify causative factors for some congenital anomaly (Doering and Stewart, 1978). Inevitably, this approach cannot provide accurate information, because of the fallability of memory and of medical records, and because of the erratic way in which prescribed drugs may have been taken. Nevertheless, studies have indicated that pregnant women may take a large number of drugs. Forfar and Nelson (1973) in Scotland reported in their study of 911 women that 82 per cent were prescribed an average of 4 drugs during pregnancy. Moreover, 65 per cent of these women took an average of 1.5 self-medicated drugs; the period of drug consumption (prescribed or self-medicated) amounted to 60 per cent of the whole duration of pregnancy. Hill (1973), in a study of 156 American women, found between 3 and 29 drugs (mean 10.3) ingested during pregnancy, labour and delivery. Among these analgesics--usually containing salicylates--were the most frequently taken (64 per cent), the next were diuretics (57 per cent), followed by antihistamines (52 per cent), antibiotics--mostly penicillin-like (41 per cent), antacids (35 per cent) and sedatives (24 per cent). In a further report concerning the incidence of ingestion of so-called over-the-counter (OTC) drugs, Hill et al. (1977) found some OTC drug use in 95 per cent of the 231 pregnant women investigated. More recently a prospective study was undertaken in 168 obstetrical patients: all patients consumed at least 2 medicines; 93.4 per cent took between 5 and 32 products, and the average number of drugs used during the prenatal period was 11.0 (Doering and Stewart, 1978). Unfortunately accurate data on OTC drugs are rarely available, but it is evident that these would add considerably to the total drug intake during pregnancy. Thus, it is believed that analgesic sales are 20 times, and antacid sales 3 times higher over the

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counter than on prescription (Boethius, 1977). It is also well known that smokers ingest more drugs and other chemicals (coffee, alcohol, marijuana etc) than non-smokers (Jusko, 1978). Since tobacco smoking is considered as a primary source of drug interactions it would seem mandatory to include this habit as a basic characteristic of the women investigated. It is common experience that the better informed and educated mothers are increasingly cautious about accepting drugs during pregnancy even on medical advice, as knowledge of possible drug effects on the fetus spreads in the population it is likely that drug usage such as that reported by Forfar and Nelson (1973) and Hill (1973) will no longer be seen. Usually drug therapy is based on a genuine clinical need; yet it is very often conducted without considering that pregnancy itself produces a variety of changes in functional parameters and may therefore modify the drug handling by the pregnant woman. Furthermore, the studies on placental drug transfer indicate that most--if not all--drugs can cross the placenta with ease and the fetus must be exposed to a variety of active compounds. Thus, when a pregnant woman takes a drug, her fetus becomes a possibly unwanted and non-benefiting drug recipient (Stern, 1975). There is also a more positive aspect of this problem: the recently increasing knowledge and improving ability to diagnose fetal disease has introduced the idea of treating the fetus in utero by giving drugs to the pregnant mother (Yaffe and Stern, 1976). At present this is still mostly an exploratory procedure in which the prediction of the time course of drug concentrations in the maternal-fetal unit must be a prerequisite for rational therapy of the fetus.

5. SUMMARY The pregnant woman is frequently exposed to pharmacologically active compounds, either accidentally or for medical purposes. This review has emphasized that data from pharmacokinetic studies in n0n-pregnant and pregnant women show many differences, and kinetic parameters may not be interchanged without major corrections. An attempt is made to describe those physiological adjustments made by the mother which might be expected to influence drug pharmacokinetics. The mechanisms of absorption, distribution, metabolism and excretion of many drugs undergo profound modifications. This is due to pregnancy-specific alterations of the functional capacities and performances of many organ systems, the development of new body water compartments and metabolically active units, as well as haemodynamic changes and biochemical adaptations. The mechanisms responsible for those changes are not yet fully understood, but some modifications, such as the reduced motility of stomach and gut, water retention, the increase and redistribution of the cardiac output, gestational hyperventilation and alterations of certain enzyme activities, are probably an expression of pregnancy changes in endocrine function. Gastro-intestinal, renal, pulmonary or hepatic drug kinetics will thus be modified in different, gestation-specific ways. In addition to the influence of physiological adaptations of pregnancy on maternal drug handling, fetal drug exposure is discussed. Experimental access to the feto-placental unit in man is restricted for technical, legal and ethical reasons, and single point determinations of maternal and fetal drug concentrations are usually the only available data. Pharmacokinetic information on the intrauterine compartments gained by such investigations are obviously of limited value. Serial determinations of maternal-fetal drug concentration-time courses, which would be of much greater interest, are however practically impossible to perform. To overcome this drawback the introduction of pharmacokinetic computer models is proposed. This allows the maximum use of information obtained from different studies and the establishment of composite data. The results become more meaningful, when

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integrated into suitable models, representing the compartmental aspects of the fetomaternal unit and the feto-maternal drug interrelation. An index of relative exposure of the fetus to a particular drug may thus be approximated. This index could not only be useful in avoiding unwanted drug side-effects on the fetus, but also in designing intrauterine treatment schedules. REFERENCES ADLERCREUTZ, H., SVANBORG,A. and ANBERG, /~. (1967) Recurrent jaundice in pregnancy. I. A clinical and ultrastructural study. Am. J. Med. 42: 335-340. ALAILY, A. B. and CAROLL, K. B. (1978) Pulmonary ventilation in pregnancy. Br. J. Obstet. Gynaec. 85: 518-524. AMES, B. N., SIMS, P. and GROVER, P. L. (1972) Epoxides of carcinogenic polycyclic hydrocarbons are frameshift mutagens. Science 176: 47-49. AMON, I. and AMON, K. (1976) Zum IJbertritt yon Arzneimitteln in das Fruchtwasser. Zbl. Gyn~ik. 98: 961-969. ANTON, A. H. 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