- Email: [email protected]
Chapter 5 Pharmacology in Space: Pharmacokinetics
Chapter 5
PHARMACOLOGY IN SPACE: PHARMACOKINETlCS
S . Saivin. A . Pavy-Le Traon. C . Soulez.LaRivi&-e. A . Guell. and G . Houin I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Membrane Passage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B . Effects of Route of Administration . . . . . . . . . . . . . . . . . . . . . 111. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. BloodFlow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Physical Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Elimination of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Hepatic Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . B . Renal Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Conclusions and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Advances in Space Biology and Medicine Volume 6. pages 107-121 Copyright 0 1997 by JAI Press Inc All rights of reproduction in any form reserved ISBN: 0-7623-0147-3
.
.
107
108 108 109 109 114 114 115 116 116 117 118 118 120 120
S. SAlVlN et at.
108
1. INTRODUCTION During spaceflight the human organism undergoes various physiological modifications due to its adaptation to weightlessness. Some of these modifications last only a brieftime, while others persist during the entire flight. During this adaptation process the human organism reaches a new state of homeostasis. The physiologjcal and biochemical modifications taking place during spaceflight can be chronologically divided in three phases: the adaptation phase, the equilibrium phase and the landing phase. Figure 1 illustrates the most important modifications occurring in microgravity.I From a pharmacokinetic point of view, similar physiological changes occurring on Earth are well known to greatly modify drug disposition. To some extent it is possible to extrapolate from the pharmacokinetic changes observed on Earth to what may be expected to happen to drug disposition in space. The process of disposition of a drug in the body can be divided in three parts: absorption at the site of administration, distribution in the tissues, and elimination by metabolism and excretion. It is necessary, therefore, to know what will happen in weightlessness to absorption, distribution and elimination for each route of administration.2
II. ABSORPTION Absorption is the first step of drug disposition after administration. It corresponds to the appearance of the drug and in certain cases its metabolites in the circulation
IRREVERSIBLE PROCESSES
I
I
FLUIDS AND ELECTROLYTES
REDBLOOOCELLWASD
09
set Point 1.p Set Point
3
4
6
6
POW OF ADUTATIUU
Time suls (months)
figure 1. Time course of physiological shifts during spaceflight according to Nico1
gossian.
Pharmacology in Space: Pharmacokinetics
109
from the site of administration. The rate of absorption and the amount absorbed characterize the mechanisms involved in absorption. These are a function of the form in which the drug is presented, the membranes through which it passes, and the site of loss. In pharmacokinetics, the rate of absorption and the absorbed amount are characterizedby the bioavailability of the drug. It includesthe ‘first pass effect’, which is defined as any mechanism responsible for a loss of drug between the site of administration and the circulation. In most cases, the first pass effect occurs in the liver, but metabolism can occur at other sites. A. Membrane Passage
Membrane passage is required whenever a drug is administered extravascularly. This step depends on numerous parameters, such as the physicochemical properties of the drug and the specificmembrane properties. Specific cases are the blood-brain barrier and the hemo-placental barrier. Diffusion through membranesoccurs essentially according to three mechanisms: passive diffision according to Fick’s law, facilitated diffusion, and active transport. Diffusion is the most important one, and the rate of diffision is proportional to the concentration gradient across the membrane. For drugs which diffise freely, blood flow becomes the limiting factor. In weightlessness, the intrinsic ability of a drug to cross a membrane or to be actively transported is unlikely to be changed, but the blood flow in a specific tissue may be modified. Membrane permeability may also be reduced by local edema due to redistribution of fluid.3 B. Effects of Route of Administration
Routes of administration, their specific sites of loss and the different steps involved may influence the bioavailability of a drug, as illustrated in Figure 2. Weightlessness may have specific effects for each route of administration. Intravenous Route
The intravenous route is considered as the reference mode of administration, since the drug is directly introduced into the circulation and thereupon the entire administered dose is available to induce its pharmacological effect. An exception is the ability of the lungs to metabolize drugs such as norhiptyline, d-methadone, mescaline or ibuter01.~In this case, a first pass will occur before the drug reaches the pharmacological target organ, and the corresponding effect will be decreased when compared to arterial administration. Microgravity may influence lung metabolism by a possible increase in the perfusion rate of this Subcutaneous and Intramuscular Routes
Absorption after subcutaneous or intramuscular injection depends on blood flow and muscle activity. In microgravity, redistribution of the blood volume may
S. SAlVlN et al.
110
increase the blood flow in the upper part of the body and decrease it in the lower part. Therefore, bioavailability may vary depending on the site of injection. This may also affect the amount of drug metabolized before the remainder reaches the general circulation. In space,muscle atrophy,characterizedby a reduction in muscle strength, tone and endurance, has been reported.'+ Intramuscular injections of promethazine have been performed during a US. spaceflight with better efficacy than on Earth and without any sign of toxicity." However, since bioavailability of promethazine is greater after intramuscular injection than after oral ingestion," it is not possible to conclude that the better efficacy is due to a microgravity-induced change in bioavailability. Oral Route
Oral administration is best accepted by patients, and is therefore the most common route of drug administration. However, it is also the most complicated
.anzymanc a a l u Mlary excroth
1
I
LINTRAMUSCULAR RECTAL ROUTE O R A L ROUTE
AND SUBCUTANEOUS ROUT
I J
Figure 2. Variability of drug absorption in function of routes of drug administration and their site of loss.
Pharmacology in Space: Pharmacokinetics
111
route in terms of the physiological steps involved, each of which may be modified in microgravity. The most important steps are dissolving of the drug in the gastro-intestinal fluid, gastric emptying, intestinal motility, absorption through the duodenal cell membranes, and passage through the liver. Gastric emptying is known to be greatly influenced by the position of the body,'* the characteristics of the pharmaceutical form of the drug, and the presence or absence of food in the intestine. In microgravity, gastric emptying may be influenced by the weightlessness of the gastric contents.I2 The absence of gravity may have a further effect, since gastric emptying can be seen as a probability occurrence with a random chance that a particle in the stomach passes through the py10rus.'~Consequently, some modification may occur in the rate of drug absorption. This may delay the gastro-intestinal transit time and also the transit motility. Intestinal absorption involves membrane crossing phenomena that may be disturbed by modifications in local blood flow or transit time. The intestine is the main site of absorption due to its large surface and the extended residence time. On Earth, after gastric emptying, changes in intestinal absorption are mainly due to differences in the intestinal blood flow. If this flow is reduced by the fluid shift in weightlessness, then intestinal drug absorption may be decreased or slowed down. Such a mechanism has been described for digoxin in patients with cardiac decompen~ation.~ However, some drugs are never fully absorbed, either because of a primary decrease in absorption through the intestinal membrane, or as the result of local metabolism by bacteria or enzymes, or by physicochemical interactions in the intestinal lumen. Table 1 lists the main drugs for which variations of intestinal absorption are classically observed on Earth. The most common example of drug interaction before absorption is the complexation of the first generation of tetracyclines with divalent cations such as calcium or magne~ium.'~ The bioavailability of this antibiotic may thus be significantlyreduced by concomitant administration Table 1. Drugs Known to be Variously Absorbed from the Gastro-Intestinal Tract Aspirin Aldosterone Chlorpromazine Dexarnethasone L-Dopa Flurazeparn Hydrocortisone lsoprenaline Methadone Metoclopramide Morphine
Pentazocine Pethidine Phenacetin Propoxyphene Progesterone Rirniterol Salicylarnide Sulfamides Terbutaline Testosterone
S. SAlVlN et al.
112
with milk or milk products. Tetracycline are present in the space pharmaceutical kits. Since the astronaut diet may contain extra calcium to compensate the bone loss with negative calcium balance occurring in space, it will be necessary to dissociate the administration of the drug and the meal. Other examples are the interactions between digoxin or warfarin with cholestyramine, of penicillamine with aluminum or magnesium ions, of digoxin with metoclopramide and propantheline, and of penicillin with n e ~ m y c i n . ' ~ There is an important phenomenon which explains why the entire dose of an orally administered drug does not reach the general circulation: the hepatic 'first pass effect'. After being fblly absorbed from the gastro-intestinal tract, the drug passes through the liver before reaching the general circulation. In the liver a substantial fraction of the drug may be metabolized to an inactive product. This is probably the most important phenomenon, both in terms of absolute amount and of variability. It can be quantified by the extraction ratio (E,) which corresponds to the fraction of the drug reaching the liver that is metabolized. The amount escaping the liver, i.e., the maximum amount reaching the circulation after oral administration, is given by:
where F represents the bioavailability. The higher the extraction ratio, the lower will be the availability and the more variable will be the absorbed amount of the drug. If enzymatic activities of the liver vary due to diurnal changes or inductiodinhibition phenomena, even a large change in E, (up to 100%) will have only little effect on the availability of drugs with a low extraction ratio. On the other hand, for drugs with a large extraction ratio, a small change in E, will lead to a large change in the amount of drug escaping the liver. Table 2 shows the drugs most sensitive to this phenomenon. For example, Table 2. Drugs Most Sensitive to Hepatic First Pass Effect Alprenolol Aspirin Cortisone Desimipramine Dopamine FIuorouraciI Hexobarbital lmipramine lsoprenaline Lidocaine Metoprolol Morphine
Nifedipine Nortryptiline Oxprenolol Oxyphenbutazone Pentazocine Pethidine Phenacetin Pindolol Propoxyphene Propranolol Salicylamide Serotonin
Pharmacology in Space: Pharmacokinetics
113
propranolol not only requires an oral dose 8 times higher than that necessary by intravenous route, but it also shows a higher variability after oral than after intravenous administration. Among these drugs, some as aspirin, lidocaine, morphine and nifedipine are usually included in the space medical kit. The upward fluid shifts and hemodynamic changes observed in space may increase the blood perfision of the liver.599For drugs with a low extraction coefficient, being blood flow independent, it is unlikely that microgravity will have a significant effect on their hepatic first pass metabolism. However, flow-dependent drugs may be metabolized more efficiently in space than on Earth, due to the higher hepatic blood flow in space. Consequently, the bioavailability of these drugs and their circulating concentrations will be lower in space, which might necessitate an increase in dosage. Sublingual and Buccal Routes
Sublingual administration is commonly used to prevent the hepatic first pass effect. Factors that may influence absorption by this route in microgravity are possible modifications of local conditions, e.g., dryness of the mouth and cephalic fluid shift. The latter may be responsible for an increased local blood flow, which may cause a rise in the rate or the amount of drug absorbed. Absorption from these two sites depends on the blood flow, and thus the previously made remarks apply. Rectal Route
On Earth, absorption after rectal administration is variable, particularly because the hepatic first pass effect is different in terms of the veins involved in this mode of drug absorption. In microgravity, changes in the hepatic first pass effect may influence drug bioavailability, as previously described for the oral route. Percutaneous Route
Percutaneous administration does not involve the hepatic first pass effect, but the fluid shift may modify the local blood flow. Drug absorption may then depend on the site of administration. At this time the importance of such changes is difficult to predict. The local environment, such as dryness of the skin or cutaneous diseases, may also affect the absorption. Pulmonary and Nasal Route
Absorption through lungs and nose depends on the local blood flow, which will probably be influenced by the occurrence of a fluid shift. The resulting effects are again difficult to predict. After pulmonary administration, the drug must reach the capillary membrane, which is achieved by microdispersion of the drug vehicle. Microgravity may modify the characteristics of the dispersion, and thus also the amount of drug reaching the pulmonary membrane.
S. SAlVlN et al.
114
111. DlSTRl BUTlON Distribution is the process by which a drug is transferred from the blood to the interstitial fluids and the various tissues of the organism. Many factors may influence the distribution of a drug, and these could potentially be influenced by microgravity. On Earth, the main factors are the physicochemical properties of the drug, the membrane composition, the binding to tissue and plasma proteins, and the blood flow in the tissues. Protein binding and blood flow, as well as the effect of exercise, will be discussed in some detail. A. Protein Binding
Protein binding is an important phenomenon, occurring with endogenous as well as exogenous compounds. Protein molecules are always large compared to the drug molecule, 100- to 1000-fold larger. Therefore, the drug may bind to different specific sites on a given protein molecule. This binding may be saturable or non-saturable and have a high or low affinity and specificity, depending on the nature of the chemical link and the fit between drug and protein molecule. Binding is generally reversible, so that the free and bound fractions are in equilibrium with each other. The main proteins in blood, which bind circulatingdrugs or endogenous compounds, are albumin, a 1-glycoprotein and lipoproteins (Table 3). There exist a few proteins in blood plasma, which specifically bind a particular substance, like the steroid transcortin. Protein binding is an important phenomenon in pharmacokinetics, since only the free fraction of the drug is able to diffise and is therefore likely to be active or to be metabolized. The distribution of drugs is greatly influenced by binding to plasma and tissue proteins. Some changes in protein concentrations during spaceflight have been reported; these may influencedrug binding. If protein binding is non-saturable in the usual ranges of plasma protein and drug concentrations,a decrease in protein concentration will lead to little change in free and bound drug concentrations. If the protein binding capacity is near saturation, a reduction of the concentration of this protein may lead to saturation and consequently to an increase in the free active drug fraction. A similar effect will be observed when the drug dosage is increased. In microgravity, a decrease in total body water is observed, which is responsible for an increase in the concentration of hemoglobin and other blood proteins through hemoconcentration. Theoretically, the increase in protein concentrations will reduce the free fraction of drugs, but the hemoconcentration will in turn probably increase the total drug concentrations. As a consequence, the free drug concentration may be virtually unchanged. However, for drugs that are highly bound in tissues, the overall equilibrium can be modified and the bound drug in the tissues could be larger than on Earth.
115
Pharmacology in Space: Pharmacokinetics
Table 3. Protein Binding of Drugs NON-SATURABLE
SATURABLE
WEAK ACIDS to ALBUMIN: Warfarin Acenocoumarol Furosemide Diazepam
to ALBUMIN: Valproic acid Salicylic acid Phenylbutazone Clofibric acid WEAK BASES
to ALBUMIN:
to a1 -ACID G LYCOPROTEIN:
Quinidine Rifarnpicin platelet antiagregants
Quinidine platelet antiagregants Lidocaine Disopyramide lmipramine Erythromycin beta blockers
to LIPOPROTEINS: Quinidine platelet antiagregants beta blockers Rifampicin
6. Blood Flow
Blood flow regulates the rate of entry in and the output of drugs from tissues. It is more involved in the rate of distribution than in its intensity. As shown in Table 4, the tissue perfusion rates vary widely in the organism, from 0.025 ml.min-'.g-' for peripheral fat to 10 ml.min-l.g-l for lung. Obviously, when comparing individual organ flows, the organ size must be taken into account. For example, the muscle perfusion rate is low, 0.025 ml.min-'.g-l, but its total blood flow is as large as 750 ml.min-l. On the other hand, the cardiac perfusion rate of 0.6 ml.min-l.g-l is 24 x that of muscle, but the total cardiac blood flow of 4 ml.min-' is 190 x lower than in muscle.'6 The higher the perhsion rate of a tissue, the faster the equilibrium between drug inflow and outflow will be reached. During spaceflight, the fluid volume may be decreased by dehydration after vomiting induced by space motion sickness. The fluid shift is estimated to be 1 liter from each leg." This is probably the most important factor leading to changes in distribution,blood flow and tissue or protein binding. A quantitative prediction of an eventual perturbation of the blood flow in different regions of the body in space is not possible, because there is also a small increase in heart rate and a slight decrease in stroke volume and blood pressure."
S. SAlVlN et al.
116
Table 4. Local Blood Flow and Perfusion Rates of Various Tissues Organflissue Adrenal glands Bone Brain Fat tissues
Heart Kidneys Liver Lungs Inactive Muscle Skin Thyroid gland Total body
Body Volume %
0.03 16 2
10 0.5 0.4
2.3 0.7 42
ia
0.03
100
Blood Flow mI.min-’ 25 250
700 200 200 1100 1350 5000 750 300 50 5000
Perfusion Rate rn1.rnin-l .g-’ of Tissue
1.2 0.02
0.5 0.03 0.6 4 0.8 10
0.025 0.024 2.4
0.071
If there are changes in blood flow, an increase will probably induce a faster distribution of drugs, while in areas with a decreased blood flow the distribution will be slowed. Changes in tissue volumes will influence tissue distribution. Therefore, in space the ratio of adipose to muscle tissue may increase due to muscle atrophy. On Earth cardiac decompensation is known to reduce the volume of distribution of several drugs, such as dihydroquinidine, disopyramide, lidocaine, procainamide, and q~inidine.~ C. Physical Exercise
During spaceflight, crewmembers carry out physical exercise as a countermeasure to cardiovascular and musculoskeletal deconditioningduring the flight and to orthostatic intolerance upon landing. Few studies have been performed on the influence of exercise upon the pharmacokinetic disposition of drugs. The intensity of the exercise increases the blood flow of the active muscles with simultaneous reduction in the blood flow in inactive regions.” Therefore,the distribution of drugs may be modified by exercise. Furthermore, physical exercise is known to mobilize free fatty acids from adipose tissue, and thus to increase their concentration in the blood plasma. As these compounds are known to displace drugs from their binding sites on albumin, this process is likely to affect drug distribution.*’
IV. EllMlNATlON OF DRUGS Drug elimination may occur by two mechanisms: metabolism and excretion. The liver is the organ most frequently involved in drug metabolism. Excretion of drugs and their metabolites is generallyperformed by the kidney. In both mechanisms the
Pharmacology in Space: Pharmacokinetics
117
unbound fraction of the drug is generally cleared. Therefore, protein binding of the drug may be an important parameter. For drugs with a high extraction ratio, blood flow will largely determine their elimination. A. Hepatic Elimination
The liver acts on drug disposition through the hepatic first pass effect, metabolic transformation,and biliary excretion.Metabolic transformation of a drug generally leads to a more hydrophilic compound, which will be more easily cleared by the kidney. Drug metabolites may be equally, less or more effective and toxic than the parent compound. Drug transformations are enzymatic reactions, which are subject to intra- and inter-individual variations. The intra-individual variations observed in drug metabolism are induction or inhibition of the responsible enzymes by drugs or environmental factors. Autophenomena have been described. Inter-individual variations are due to genetic polymorphism involved in many enzymatic reactions. As biotransformations are enzymatic processes, they follow the Michaelis-Menten equation. When the plasma concentration is low, the reaction is roughly linear. When it is high, saturation may occur, as has been observed for alcohol and phenytoin kinetics.2' In that case, a small increase in dose will induce a large increase in plasma concentration, and thereby in the drug effect. Biliary excretion is generally a passive phenomenon, which corresponds to a negligibleroute of excretion. An active secretion has been described for some drugs such as tetracyclines and veralipride, for which very high concentrations were observed in the bile. In that case biliary excretion becomes a significant route of elimination. After gallbladder contraction, the excreted drug reaches the intestinal tract and may there be re-absorbed. This is the entero-hepatic cycle which may occur several times during the day. Hepatic clearance represents the overall capacity of the liver to metabolize a drug. It is a function of the intrinsic ability of the liver to metabolize the drug (intrinsic Clearance),of the unbound fraction of the drug, and of the hepatic blood flow. When drugs exhibit a high extraction ratio, their hepatic clearance depends only on the hepatic blood In microgravity, this may be modified by the fluid shift. Hepatic clearanceof drugs with low hepatic extraction ratio and low protein binding are only influenced by induction or inhibition mechanisms,which are generally due to the drug itself or to other co-administrated drugs. This problem is not specific to the microgravity environment. Drugs with low extraction ratio and high protein binding are influenced by the intrinsic metabolic capacities of the liver and the free fraction of the drug. These two parameters may be modified by microgravity. If the perfusion rate of the liver is modified, drugs with high extractionratio show a variable hepatic clearance. During bedrest studies, no change was observed in the hepatic blood f10w.23,24Inflight experiments are needed before definitive conclusions about the situation in space can be drawn.
118
S. SAlVlN et al.
B. Renal Excretion Renal excretion of drugs is always executed by glomerular filtration. modified by tubular secretion and reabsorption. Glomerular filtration is a passive phenomenon for small molecules, while proteins are not filtered. Therefore, only the free fraction of a drug can pass through the glomerular membrane, which means that changes in protein binding may affect glomerular filtration. Tubular secretion is an active and saturable process, which may be subject to competitive interaction with other compounds, including endogenous substances. Tubular reabsorption is essentially a passive mechanism following the concentration gradient. The pH of the urine is an important factor, since the only the unionized form is able to diffise. During spaceflight the urine pH may be changed by the different way of eating and drinking. One of the consequences of weightlessness is a decrease in renal plasma which may lower the glomerular filtration rate. The renal vascular resistance in the kidney is decreased in the head-down tilt test without c~untermeasure.~’ These changes have been shown to decrease the renal clearance. For a drug with low renal extraction ratio these changes may be important, since they may lead to a higher plasma concentration for the drug in space than observed on Earth at the same dosage. Changes in the diuresis and the renal blood flow may also decrease the excretion of some drugs. The bone demineralization process increases calcium excretion with a consequently raised risk of kidney stones. This can cause local injuries and infections. The presence ofkidney stones in the urinary tract will decrease glomerular filtration and may increase the ability of drugs to permeate through the glomerular membrane. With the occurrence of infection, the renal pH may increase, which could change drug reabsorption. In the case of a weakly acidic drug its reabsorption and thus its plasma concentration will decrease. The opposite changes will occur with weakly basic drugs.
V. CONCLUSIONS AND SUMMARY The possible pharmacokinetic mechanisms affected by microgravity are listed in Table 5. In studies of pharmacokinetics in humans, one has generally only access to drug concentrations in plasma and urine which are the results of several concurrent mechanisms. During weightlessness, different changes may occur in each step of the drug disposition process. The most important changes need to be identified and then predicted for the main drugs used in space. The use of a drug as a probe (Table 6 ) will permit to estimate the changes in specific pharmacokinetic parameters during spaceflight. However, this type of studies is technically difficult to carry out in space, but simulation studies on the ground are easier to perform. Two studies of hepatic blood flow showed no changes in this parameter during b e d r e ~ t ? but ~ . ~a~more recent study showed changes in
119
Pharmacology in Space: Pharmacokinetics
Table 5. Pharrnacokinetic Mechanisms Possibly Affected by Microgravit y ABSORPTION Absorption rate Amount PROTEIN BINDING DISTRIBUTION
METABOLISM
EXCRETION
Gastric emptying (oral route) Blood flow (all routes) Vomiting (space motion sickness) Blood flow (First pass effect) Fluid loss Modifications in muscular/adipose ratio Modifications in blood flow Modifications in protein binding Blood flow First pass effect Enzymatic induction or inhibition Modifications in protein binding Modifications in blood flow Modifications in protein binding Urine pH
Table 6. Probes in Pharrnacokinetics Drugs
Mechanism GASTRIC EMPTYING HEPATIC FIRST PASS EFFECT PROTEIN BINDING
DISTRIBUTION METABOLISM High extraction ratio drugs Low extraction ratio drugs low protein binding high protein binding RENAL EXCRETION Glomerular filtration Tubular secretion acidic drugs basic drugs Tubular reabsorption
Acetaminophen, metoclopramide, labeled solid meals Morphine, propranolol, trinitrate molecules, Nifedipin, Nortryptiline Valproic acid, clofibrate, warfarin, propranolol, carbamazepine, disopyramide, phenytoin, phenylbutazone, salicylic acid, lidocaine, beta blockers, erythromycin Non-steroidal anti-inflammatory drugs, erythromycin, propranolol Lidocaine, indocyanine green, propranolol, morphine, nitroglycerine, pentazocine, pethidine, propoxyphene, salicylamide Antipyrine, acetaminophen (glucuronidation), theophyl Iine Warfarin, phenytoin, diazepam Creatinine, inulin Para-aminohippuric acid, furosemide, penicillin, salicylates Morphine, neostigmine, quinine Hydrochlorothiazide, salicylates, methylamphetamine
S . SAlVlN et al.
120
lidocaine disposition during a four-day head-down-tilt.26 Due to the large differences between individuals, pharmacokinetic changes must be fairly large (> 1020%) to be observed in studies with probes. To detect a small change in weightlessness will require a number of subjects far higher than can be achieved in spaceflight. In summary, spaceflight is known to change many physiological parameters. The pharmacokinetics of drug disposition is determined by the combination of several complex phenomena. Each step of this process may be influenced by physiopathological changes occurring in spaceflight. This review shows how from a theoretical point of view absorption, distribution and elimination of drugs may be affected by weightlessness. The physiological changes most frequently involved in these modifications are the changes in blood flow due to the fluid shift.
ACKNOWLEDGMENTS This work was supported by the PHARMEMSI Study and contract NO961 1/91/FL from the European Space Agency.
REFERENCES 1. Nicogossian, A.E. Overall physiological response to space flight. In: Space Physiology and Medicine. 2nd ed., pp. 13!&153. Lea & Febiger, Philadelphia, 1989.
2. Pavy-Le Traon, A,, Giiell, A., Saivin. S., Houin, G., Soulez-LaRiviere, C., Pujos, M. The use of medicaments in space-Therapeutic measures and potential impact of pharmacokinetics due to weightlessness. ESA Journal, 1833-50, 1994. 3. Lesne, M. Influence de la decompensation cardiaque sur les parametres pharmacocinetiques des medicaments. SEMPER, 11:26-29, 1988. 4. Labaune. J.P. Pharmacocinbique. Principes Fondamentau. Masson, Pans. 1984. 5. Charles, J.B., Lathers, C.M. Cardiovascular adaptation to spaceflight. Journal of Clinical Pharmacology, 31:101&I 023, 1991. 6. Lathers, C.M.,Charles, J.B., Elton, K.F., Holt,T.A., Mukai,C.. Bennett, B.S..Bungo, M.W. Acute haemodynamic responses to weightlessness in humans. Journal of Clinical Pharmacology, 31:615-627, 1991. 7. Lathers, C.M., Charles, J.B., Bungo, M.W. Pharmacology in space. Part 1 Influence of adaptative changes on pharmacokinetics. Trends in Pharmacological Science, 10: 193-200, 1989. 8. Leach, C.S., Cintron, N.M., Krauhs, J.M. Metabolic changes observed in astronauts. Journal of Clinical Pharmacology, 31:921-927, 1991. 9. Leach, C.S., Inners, D.L., Charles, J.B. Changes in total body water during space flight. Journal ofCIinical Pharmacology, 31:lOOl-1006, 1991. 10. Bagian, J.P. First intramuscular administration in the U.S. space program. Journal of Clinical Pharmacology, 31:920, 1991. 11. Schwinghammer, T.L., Juhl, R.P. Comparison of the bioavailability of oral, rectal and intramuscular promethazine. Biopharmaceuticsand Drug Disposition, 5:185-194, 1984. 12. Backon, J., Hoffman, A. The lateral decubitus position may affect gastric emptying through an autonomic mechanism: the skin pressure vegetative reflex. British Journal of Clinical Pharmacology, 32: 138, 199 1.
Pharmacology in Space: Pharmacokinetics
121
13. Amidon, G.L., Debrincat, G.A., Najib, N. Effects ofgravity on gastric emptying, intestinal transit, and drug absorption. Journal of Clinical Pharmacology, 31:96W73, 1991. 14. Neuvonen, P.J. Interactions with absorption of tetracyclines. Drugs, 11:45, 1976. 15. Stockley, I.H. Drug Interactions.A Source BookofDrug Interactions, Their Mechanisms. Clinical Importance and Management. Blackwell, London, 2nd ed., 199 1. 16. Rowland, M., Tozer, T.N. ClinicalPharmacokinetics. ConceplsandApplications. Lea and Febiger, Philadelphia, 2nd ed., 1989. 17. Moore, T.P., Thornton, W.E. Inflight and postflight fluid shifts measured by legs volume changes. In: Results of the lije sciences DSOS conducted about the Space Shuttle 1981-1986 (NASA Editorial Review Board), pp. 59-65. NASA TM-58-280, NASA, Washington, D.C., 1987. 18. Mulvagh, S.L., Charles, J.B., Riddle, J.M., Rehbein, T.L., Bungo, M.W. Echocardiographic evaluation of the cardiovascular effects of short duration spaceflight. Journal of Clinical Pharmacology, 31:102&1026, 1991. 19. Iversen, P.O., Standa, M.. Nicolaysen. G. Marked regional heterogeneity in blood flow within a single skeletal muscle at rest and during exercise hyperaemia in the rabbit. Acta PhysiologiaScandinavica. 136:17-28, 1989. 20. Ylitalo, P. Effect of exercise on pharmacokinetics. Annals of Medicine, 23:28%294, 1991. 21. Winter, M.E., Tozer, T., Phenytoin. In: AppliedPharmacokinetics (W.G. Evans, J.J. Schentag, W.J. Jusko, Eds.), pp. 493-539.2nd ed., Applied Therapeutics, Spokane, WA, 1986. 22. Wilkinson, G.R.. Shand, D.G. A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics, 18:377-390, 1975. 23. Putcha, L. Cintron, N.M., Vanderploeg, J.M.. Chen, Y., Habis, J., Adler, J. Effect ofantiorthostatic bed rest on hepatic blood flow in man. Aviation Space EnvironmentalMedicine.59:306-308,1980. 24. Kates, R.E., Harapat, S.R., Keefe. D.L., Goldwater, D., Harrison, D.C. Influence of prolonged recumbency on drug disposition. Clinical Pharmacology and Therapeutics,28:624428, 1980. 25. Arbeille, P., Gauquelin, G., Pottier, J.M., Pourcelot, L., Giiell. A,, Gharib, C. Results of a 4-week head-down tilt with and without LBNP countermeasure: I1 Cardiac and peripheral hemodynamicscomparison with a 25 day spaceflight. Aviation Space Environmental Medicine, 63:%13, 1992. 26. Saivin, S., Pay-Le Traon, A,, Cornac, A,, Guell, A,, Houin, G. Impact of a four-day-head-down tilt (-6")on LidocaYne pharmacokinetics used as probe to evaluate hepatic blood flow. Journal of Clinical Pharmacology, 35697-704, 1995; erratum 351059, 1995.
PHARMACOLOGY IN SPACE: PHARMACOKINETlCS
S . Saivin. A . Pavy-Le Traon. C . Soulez.LaRivi&-e. A . Guell. and G . Houin I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Membrane Passage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B . Effects of Route of Administration . . . . . . . . . . . . . . . . . . . . . 111. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. BloodFlow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Physical Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Elimination of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Hepatic Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . B . Renal Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Conclusions and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Advances in Space Biology and Medicine Volume 6. pages 107-121 Copyright 0 1997 by JAI Press Inc All rights of reproduction in any form reserved ISBN: 0-7623-0147-3
.
.
107
108 108 109 109 114 114 115 116 116 117 118 118 120 120
S. SAlVlN et at.
108
1. INTRODUCTION During spaceflight the human organism undergoes various physiological modifications due to its adaptation to weightlessness. Some of these modifications last only a brieftime, while others persist during the entire flight. During this adaptation process the human organism reaches a new state of homeostasis. The physiologjcal and biochemical modifications taking place during spaceflight can be chronologically divided in three phases: the adaptation phase, the equilibrium phase and the landing phase. Figure 1 illustrates the most important modifications occurring in microgravity.I From a pharmacokinetic point of view, similar physiological changes occurring on Earth are well known to greatly modify drug disposition. To some extent it is possible to extrapolate from the pharmacokinetic changes observed on Earth to what may be expected to happen to drug disposition in space. The process of disposition of a drug in the body can be divided in three parts: absorption at the site of administration, distribution in the tissues, and elimination by metabolism and excretion. It is necessary, therefore, to know what will happen in weightlessness to absorption, distribution and elimination for each route of administration.2
II. ABSORPTION Absorption is the first step of drug disposition after administration. It corresponds to the appearance of the drug and in certain cases its metabolites in the circulation
IRREVERSIBLE PROCESSES
I
I
FLUIDS AND ELECTROLYTES
REDBLOOOCELLWASD
09
set Point 1.p Set Point
3
4
6
6
POW OF ADUTATIUU
Time suls (months)
figure 1. Time course of physiological shifts during spaceflight according to Nico1
gossian.
Pharmacology in Space: Pharmacokinetics
109
from the site of administration. The rate of absorption and the amount absorbed characterize the mechanisms involved in absorption. These are a function of the form in which the drug is presented, the membranes through which it passes, and the site of loss. In pharmacokinetics, the rate of absorption and the absorbed amount are characterizedby the bioavailability of the drug. It includesthe ‘first pass effect’, which is defined as any mechanism responsible for a loss of drug between the site of administration and the circulation. In most cases, the first pass effect occurs in the liver, but metabolism can occur at other sites. A. Membrane Passage
Membrane passage is required whenever a drug is administered extravascularly. This step depends on numerous parameters, such as the physicochemical properties of the drug and the specificmembrane properties. Specific cases are the blood-brain barrier and the hemo-placental barrier. Diffusion through membranesoccurs essentially according to three mechanisms: passive diffision according to Fick’s law, facilitated diffusion, and active transport. Diffusion is the most important one, and the rate of diffision is proportional to the concentration gradient across the membrane. For drugs which diffise freely, blood flow becomes the limiting factor. In weightlessness, the intrinsic ability of a drug to cross a membrane or to be actively transported is unlikely to be changed, but the blood flow in a specific tissue may be modified. Membrane permeability may also be reduced by local edema due to redistribution of fluid.3 B. Effects of Route of Administration
Routes of administration, their specific sites of loss and the different steps involved may influence the bioavailability of a drug, as illustrated in Figure 2. Weightlessness may have specific effects for each route of administration. Intravenous Route
The intravenous route is considered as the reference mode of administration, since the drug is directly introduced into the circulation and thereupon the entire administered dose is available to induce its pharmacological effect. An exception is the ability of the lungs to metabolize drugs such as norhiptyline, d-methadone, mescaline or ibuter01.~In this case, a first pass will occur before the drug reaches the pharmacological target organ, and the corresponding effect will be decreased when compared to arterial administration. Microgravity may influence lung metabolism by a possible increase in the perfusion rate of this Subcutaneous and Intramuscular Routes
Absorption after subcutaneous or intramuscular injection depends on blood flow and muscle activity. In microgravity, redistribution of the blood volume may
S. SAlVlN et al.
110
increase the blood flow in the upper part of the body and decrease it in the lower part. Therefore, bioavailability may vary depending on the site of injection. This may also affect the amount of drug metabolized before the remainder reaches the general circulation. In space,muscle atrophy,characterizedby a reduction in muscle strength, tone and endurance, has been reported.'+ Intramuscular injections of promethazine have been performed during a US. spaceflight with better efficacy than on Earth and without any sign of toxicity." However, since bioavailability of promethazine is greater after intramuscular injection than after oral ingestion," it is not possible to conclude that the better efficacy is due to a microgravity-induced change in bioavailability. Oral Route
Oral administration is best accepted by patients, and is therefore the most common route of drug administration. However, it is also the most complicated
.anzymanc a a l u Mlary excroth
1
I
LINTRAMUSCULAR RECTAL ROUTE O R A L ROUTE
AND SUBCUTANEOUS ROUT
I J
Figure 2. Variability of drug absorption in function of routes of drug administration and their site of loss.
Pharmacology in Space: Pharmacokinetics
111
route in terms of the physiological steps involved, each of which may be modified in microgravity. The most important steps are dissolving of the drug in the gastro-intestinal fluid, gastric emptying, intestinal motility, absorption through the duodenal cell membranes, and passage through the liver. Gastric emptying is known to be greatly influenced by the position of the body,'* the characteristics of the pharmaceutical form of the drug, and the presence or absence of food in the intestine. In microgravity, gastric emptying may be influenced by the weightlessness of the gastric contents.I2 The absence of gravity may have a further effect, since gastric emptying can be seen as a probability occurrence with a random chance that a particle in the stomach passes through the py10rus.'~Consequently, some modification may occur in the rate of drug absorption. This may delay the gastro-intestinal transit time and also the transit motility. Intestinal absorption involves membrane crossing phenomena that may be disturbed by modifications in local blood flow or transit time. The intestine is the main site of absorption due to its large surface and the extended residence time. On Earth, after gastric emptying, changes in intestinal absorption are mainly due to differences in the intestinal blood flow. If this flow is reduced by the fluid shift in weightlessness, then intestinal drug absorption may be decreased or slowed down. Such a mechanism has been described for digoxin in patients with cardiac decompen~ation.~ However, some drugs are never fully absorbed, either because of a primary decrease in absorption through the intestinal membrane, or as the result of local metabolism by bacteria or enzymes, or by physicochemical interactions in the intestinal lumen. Table 1 lists the main drugs for which variations of intestinal absorption are classically observed on Earth. The most common example of drug interaction before absorption is the complexation of the first generation of tetracyclines with divalent cations such as calcium or magne~ium.'~ The bioavailability of this antibiotic may thus be significantlyreduced by concomitant administration Table 1. Drugs Known to be Variously Absorbed from the Gastro-Intestinal Tract Aspirin Aldosterone Chlorpromazine Dexarnethasone L-Dopa Flurazeparn Hydrocortisone lsoprenaline Methadone Metoclopramide Morphine
Pentazocine Pethidine Phenacetin Propoxyphene Progesterone Rirniterol Salicylarnide Sulfamides Terbutaline Testosterone
S. SAlVlN et al.
112
with milk or milk products. Tetracycline are present in the space pharmaceutical kits. Since the astronaut diet may contain extra calcium to compensate the bone loss with negative calcium balance occurring in space, it will be necessary to dissociate the administration of the drug and the meal. Other examples are the interactions between digoxin or warfarin with cholestyramine, of penicillamine with aluminum or magnesium ions, of digoxin with metoclopramide and propantheline, and of penicillin with n e ~ m y c i n . ' ~ There is an important phenomenon which explains why the entire dose of an orally administered drug does not reach the general circulation: the hepatic 'first pass effect'. After being fblly absorbed from the gastro-intestinal tract, the drug passes through the liver before reaching the general circulation. In the liver a substantial fraction of the drug may be metabolized to an inactive product. This is probably the most important phenomenon, both in terms of absolute amount and of variability. It can be quantified by the extraction ratio (E,) which corresponds to the fraction of the drug reaching the liver that is metabolized. The amount escaping the liver, i.e., the maximum amount reaching the circulation after oral administration, is given by:
where F represents the bioavailability. The higher the extraction ratio, the lower will be the availability and the more variable will be the absorbed amount of the drug. If enzymatic activities of the liver vary due to diurnal changes or inductiodinhibition phenomena, even a large change in E, (up to 100%) will have only little effect on the availability of drugs with a low extraction ratio. On the other hand, for drugs with a large extraction ratio, a small change in E, will lead to a large change in the amount of drug escaping the liver. Table 2 shows the drugs most sensitive to this phenomenon. For example, Table 2. Drugs Most Sensitive to Hepatic First Pass Effect Alprenolol Aspirin Cortisone Desimipramine Dopamine FIuorouraciI Hexobarbital lmipramine lsoprenaline Lidocaine Metoprolol Morphine
Nifedipine Nortryptiline Oxprenolol Oxyphenbutazone Pentazocine Pethidine Phenacetin Pindolol Propoxyphene Propranolol Salicylamide Serotonin
Pharmacology in Space: Pharmacokinetics
113
propranolol not only requires an oral dose 8 times higher than that necessary by intravenous route, but it also shows a higher variability after oral than after intravenous administration. Among these drugs, some as aspirin, lidocaine, morphine and nifedipine are usually included in the space medical kit. The upward fluid shifts and hemodynamic changes observed in space may increase the blood perfision of the liver.599For drugs with a low extraction coefficient, being blood flow independent, it is unlikely that microgravity will have a significant effect on their hepatic first pass metabolism. However, flow-dependent drugs may be metabolized more efficiently in space than on Earth, due to the higher hepatic blood flow in space. Consequently, the bioavailability of these drugs and their circulating concentrations will be lower in space, which might necessitate an increase in dosage. Sublingual and Buccal Routes
Sublingual administration is commonly used to prevent the hepatic first pass effect. Factors that may influence absorption by this route in microgravity are possible modifications of local conditions, e.g., dryness of the mouth and cephalic fluid shift. The latter may be responsible for an increased local blood flow, which may cause a rise in the rate or the amount of drug absorbed. Absorption from these two sites depends on the blood flow, and thus the previously made remarks apply. Rectal Route
On Earth, absorption after rectal administration is variable, particularly because the hepatic first pass effect is different in terms of the veins involved in this mode of drug absorption. In microgravity, changes in the hepatic first pass effect may influence drug bioavailability, as previously described for the oral route. Percutaneous Route
Percutaneous administration does not involve the hepatic first pass effect, but the fluid shift may modify the local blood flow. Drug absorption may then depend on the site of administration. At this time the importance of such changes is difficult to predict. The local environment, such as dryness of the skin or cutaneous diseases, may also affect the absorption. Pulmonary and Nasal Route
Absorption through lungs and nose depends on the local blood flow, which will probably be influenced by the occurrence of a fluid shift. The resulting effects are again difficult to predict. After pulmonary administration, the drug must reach the capillary membrane, which is achieved by microdispersion of the drug vehicle. Microgravity may modify the characteristics of the dispersion, and thus also the amount of drug reaching the pulmonary membrane.
S. SAlVlN et al.
114
111. DlSTRl BUTlON Distribution is the process by which a drug is transferred from the blood to the interstitial fluids and the various tissues of the organism. Many factors may influence the distribution of a drug, and these could potentially be influenced by microgravity. On Earth, the main factors are the physicochemical properties of the drug, the membrane composition, the binding to tissue and plasma proteins, and the blood flow in the tissues. Protein binding and blood flow, as well as the effect of exercise, will be discussed in some detail. A. Protein Binding
Protein binding is an important phenomenon, occurring with endogenous as well as exogenous compounds. Protein molecules are always large compared to the drug molecule, 100- to 1000-fold larger. Therefore, the drug may bind to different specific sites on a given protein molecule. This binding may be saturable or non-saturable and have a high or low affinity and specificity, depending on the nature of the chemical link and the fit between drug and protein molecule. Binding is generally reversible, so that the free and bound fractions are in equilibrium with each other. The main proteins in blood, which bind circulatingdrugs or endogenous compounds, are albumin, a 1-glycoprotein and lipoproteins (Table 3). There exist a few proteins in blood plasma, which specifically bind a particular substance, like the steroid transcortin. Protein binding is an important phenomenon in pharmacokinetics, since only the free fraction of the drug is able to diffise and is therefore likely to be active or to be metabolized. The distribution of drugs is greatly influenced by binding to plasma and tissue proteins. Some changes in protein concentrations during spaceflight have been reported; these may influencedrug binding. If protein binding is non-saturable in the usual ranges of plasma protein and drug concentrations,a decrease in protein concentration will lead to little change in free and bound drug concentrations. If the protein binding capacity is near saturation, a reduction of the concentration of this protein may lead to saturation and consequently to an increase in the free active drug fraction. A similar effect will be observed when the drug dosage is increased. In microgravity, a decrease in total body water is observed, which is responsible for an increase in the concentration of hemoglobin and other blood proteins through hemoconcentration. Theoretically, the increase in protein concentrations will reduce the free fraction of drugs, but the hemoconcentration will in turn probably increase the total drug concentrations. As a consequence, the free drug concentration may be virtually unchanged. However, for drugs that are highly bound in tissues, the overall equilibrium can be modified and the bound drug in the tissues could be larger than on Earth.
115
Pharmacology in Space: Pharmacokinetics
Table 3. Protein Binding of Drugs NON-SATURABLE
SATURABLE
WEAK ACIDS to ALBUMIN: Warfarin Acenocoumarol Furosemide Diazepam
to ALBUMIN: Valproic acid Salicylic acid Phenylbutazone Clofibric acid WEAK BASES
to ALBUMIN:
to a1 -ACID G LYCOPROTEIN:
Quinidine Rifarnpicin platelet antiagregants
Quinidine platelet antiagregants Lidocaine Disopyramide lmipramine Erythromycin beta blockers
to LIPOPROTEINS: Quinidine platelet antiagregants beta blockers Rifampicin
6. Blood Flow
Blood flow regulates the rate of entry in and the output of drugs from tissues. It is more involved in the rate of distribution than in its intensity. As shown in Table 4, the tissue perfusion rates vary widely in the organism, from 0.025 ml.min-'.g-' for peripheral fat to 10 ml.min-l.g-l for lung. Obviously, when comparing individual organ flows, the organ size must be taken into account. For example, the muscle perfusion rate is low, 0.025 ml.min-'.g-l, but its total blood flow is as large as 750 ml.min-l. On the other hand, the cardiac perfusion rate of 0.6 ml.min-l.g-l is 24 x that of muscle, but the total cardiac blood flow of 4 ml.min-' is 190 x lower than in muscle.'6 The higher the perhsion rate of a tissue, the faster the equilibrium between drug inflow and outflow will be reached. During spaceflight, the fluid volume may be decreased by dehydration after vomiting induced by space motion sickness. The fluid shift is estimated to be 1 liter from each leg." This is probably the most important factor leading to changes in distribution,blood flow and tissue or protein binding. A quantitative prediction of an eventual perturbation of the blood flow in different regions of the body in space is not possible, because there is also a small increase in heart rate and a slight decrease in stroke volume and blood pressure."
S. SAlVlN et al.
116
Table 4. Local Blood Flow and Perfusion Rates of Various Tissues Organflissue Adrenal glands Bone Brain Fat tissues
Heart Kidneys Liver Lungs Inactive Muscle Skin Thyroid gland Total body
Body Volume %
0.03 16 2
10 0.5 0.4
2.3 0.7 42
ia
0.03
100
Blood Flow mI.min-’ 25 250
700 200 200 1100 1350 5000 750 300 50 5000
Perfusion Rate rn1.rnin-l .g-’ of Tissue
1.2 0.02
0.5 0.03 0.6 4 0.8 10
0.025 0.024 2.4
0.071
If there are changes in blood flow, an increase will probably induce a faster distribution of drugs, while in areas with a decreased blood flow the distribution will be slowed. Changes in tissue volumes will influence tissue distribution. Therefore, in space the ratio of adipose to muscle tissue may increase due to muscle atrophy. On Earth cardiac decompensation is known to reduce the volume of distribution of several drugs, such as dihydroquinidine, disopyramide, lidocaine, procainamide, and q~inidine.~ C. Physical Exercise
During spaceflight, crewmembers carry out physical exercise as a countermeasure to cardiovascular and musculoskeletal deconditioningduring the flight and to orthostatic intolerance upon landing. Few studies have been performed on the influence of exercise upon the pharmacokinetic disposition of drugs. The intensity of the exercise increases the blood flow of the active muscles with simultaneous reduction in the blood flow in inactive regions.” Therefore,the distribution of drugs may be modified by exercise. Furthermore, physical exercise is known to mobilize free fatty acids from adipose tissue, and thus to increase their concentration in the blood plasma. As these compounds are known to displace drugs from their binding sites on albumin, this process is likely to affect drug distribution.*’
IV. EllMlNATlON OF DRUGS Drug elimination may occur by two mechanisms: metabolism and excretion. The liver is the organ most frequently involved in drug metabolism. Excretion of drugs and their metabolites is generallyperformed by the kidney. In both mechanisms the
Pharmacology in Space: Pharmacokinetics
117
unbound fraction of the drug is generally cleared. Therefore, protein binding of the drug may be an important parameter. For drugs with a high extraction ratio, blood flow will largely determine their elimination. A. Hepatic Elimination
The liver acts on drug disposition through the hepatic first pass effect, metabolic transformation,and biliary excretion.Metabolic transformation of a drug generally leads to a more hydrophilic compound, which will be more easily cleared by the kidney. Drug metabolites may be equally, less or more effective and toxic than the parent compound. Drug transformations are enzymatic reactions, which are subject to intra- and inter-individual variations. The intra-individual variations observed in drug metabolism are induction or inhibition of the responsible enzymes by drugs or environmental factors. Autophenomena have been described. Inter-individual variations are due to genetic polymorphism involved in many enzymatic reactions. As biotransformations are enzymatic processes, they follow the Michaelis-Menten equation. When the plasma concentration is low, the reaction is roughly linear. When it is high, saturation may occur, as has been observed for alcohol and phenytoin kinetics.2' In that case, a small increase in dose will induce a large increase in plasma concentration, and thereby in the drug effect. Biliary excretion is generally a passive phenomenon, which corresponds to a negligibleroute of excretion. An active secretion has been described for some drugs such as tetracyclines and veralipride, for which very high concentrations were observed in the bile. In that case biliary excretion becomes a significant route of elimination. After gallbladder contraction, the excreted drug reaches the intestinal tract and may there be re-absorbed. This is the entero-hepatic cycle which may occur several times during the day. Hepatic clearance represents the overall capacity of the liver to metabolize a drug. It is a function of the intrinsic ability of the liver to metabolize the drug (intrinsic Clearance),of the unbound fraction of the drug, and of the hepatic blood flow. When drugs exhibit a high extraction ratio, their hepatic clearance depends only on the hepatic blood In microgravity, this may be modified by the fluid shift. Hepatic clearanceof drugs with low hepatic extraction ratio and low protein binding are only influenced by induction or inhibition mechanisms,which are generally due to the drug itself or to other co-administrated drugs. This problem is not specific to the microgravity environment. Drugs with low extraction ratio and high protein binding are influenced by the intrinsic metabolic capacities of the liver and the free fraction of the drug. These two parameters may be modified by microgravity. If the perfusion rate of the liver is modified, drugs with high extractionratio show a variable hepatic clearance. During bedrest studies, no change was observed in the hepatic blood f10w.23,24Inflight experiments are needed before definitive conclusions about the situation in space can be drawn.
118
S. SAlVlN et al.
B. Renal Excretion Renal excretion of drugs is always executed by glomerular filtration. modified by tubular secretion and reabsorption. Glomerular filtration is a passive phenomenon for small molecules, while proteins are not filtered. Therefore, only the free fraction of a drug can pass through the glomerular membrane, which means that changes in protein binding may affect glomerular filtration. Tubular secretion is an active and saturable process, which may be subject to competitive interaction with other compounds, including endogenous substances. Tubular reabsorption is essentially a passive mechanism following the concentration gradient. The pH of the urine is an important factor, since the only the unionized form is able to diffise. During spaceflight the urine pH may be changed by the different way of eating and drinking. One of the consequences of weightlessness is a decrease in renal plasma which may lower the glomerular filtration rate. The renal vascular resistance in the kidney is decreased in the head-down tilt test without c~untermeasure.~’ These changes have been shown to decrease the renal clearance. For a drug with low renal extraction ratio these changes may be important, since they may lead to a higher plasma concentration for the drug in space than observed on Earth at the same dosage. Changes in the diuresis and the renal blood flow may also decrease the excretion of some drugs. The bone demineralization process increases calcium excretion with a consequently raised risk of kidney stones. This can cause local injuries and infections. The presence ofkidney stones in the urinary tract will decrease glomerular filtration and may increase the ability of drugs to permeate through the glomerular membrane. With the occurrence of infection, the renal pH may increase, which could change drug reabsorption. In the case of a weakly acidic drug its reabsorption and thus its plasma concentration will decrease. The opposite changes will occur with weakly basic drugs.
V. CONCLUSIONS AND SUMMARY The possible pharmacokinetic mechanisms affected by microgravity are listed in Table 5. In studies of pharmacokinetics in humans, one has generally only access to drug concentrations in plasma and urine which are the results of several concurrent mechanisms. During weightlessness, different changes may occur in each step of the drug disposition process. The most important changes need to be identified and then predicted for the main drugs used in space. The use of a drug as a probe (Table 6 ) will permit to estimate the changes in specific pharmacokinetic parameters during spaceflight. However, this type of studies is technically difficult to carry out in space, but simulation studies on the ground are easier to perform. Two studies of hepatic blood flow showed no changes in this parameter during b e d r e ~ t ? but ~ . ~a~more recent study showed changes in
119
Pharmacology in Space: Pharmacokinetics
Table 5. Pharrnacokinetic Mechanisms Possibly Affected by Microgravit y ABSORPTION Absorption rate Amount PROTEIN BINDING DISTRIBUTION
METABOLISM
EXCRETION
Gastric emptying (oral route) Blood flow (all routes) Vomiting (space motion sickness) Blood flow (First pass effect) Fluid loss Modifications in muscular/adipose ratio Modifications in blood flow Modifications in protein binding Blood flow First pass effect Enzymatic induction or inhibition Modifications in protein binding Modifications in blood flow Modifications in protein binding Urine pH
Table 6. Probes in Pharrnacokinetics Drugs
Mechanism GASTRIC EMPTYING HEPATIC FIRST PASS EFFECT PROTEIN BINDING
DISTRIBUTION METABOLISM High extraction ratio drugs Low extraction ratio drugs low protein binding high protein binding RENAL EXCRETION Glomerular filtration Tubular secretion acidic drugs basic drugs Tubular reabsorption
Acetaminophen, metoclopramide, labeled solid meals Morphine, propranolol, trinitrate molecules, Nifedipin, Nortryptiline Valproic acid, clofibrate, warfarin, propranolol, carbamazepine, disopyramide, phenytoin, phenylbutazone, salicylic acid, lidocaine, beta blockers, erythromycin Non-steroidal anti-inflammatory drugs, erythromycin, propranolol Lidocaine, indocyanine green, propranolol, morphine, nitroglycerine, pentazocine, pethidine, propoxyphene, salicylamide Antipyrine, acetaminophen (glucuronidation), theophyl Iine Warfarin, phenytoin, diazepam Creatinine, inulin Para-aminohippuric acid, furosemide, penicillin, salicylates Morphine, neostigmine, quinine Hydrochlorothiazide, salicylates, methylamphetamine
S . SAlVlN et al.
120
lidocaine disposition during a four-day head-down-tilt.26 Due to the large differences between individuals, pharmacokinetic changes must be fairly large (> 1020%) to be observed in studies with probes. To detect a small change in weightlessness will require a number of subjects far higher than can be achieved in spaceflight. In summary, spaceflight is known to change many physiological parameters. The pharmacokinetics of drug disposition is determined by the combination of several complex phenomena. Each step of this process may be influenced by physiopathological changes occurring in spaceflight. This review shows how from a theoretical point of view absorption, distribution and elimination of drugs may be affected by weightlessness. The physiological changes most frequently involved in these modifications are the changes in blood flow due to the fluid shift.
ACKNOWLEDGMENTS This work was supported by the PHARMEMSI Study and contract NO961 1/91/FL from the European Space Agency.
REFERENCES 1. Nicogossian, A.E. Overall physiological response to space flight. In: Space Physiology and Medicine. 2nd ed., pp. 13!&153. Lea & Febiger, Philadelphia, 1989.
2. Pavy-Le Traon, A,, Giiell, A., Saivin. S., Houin, G., Soulez-LaRiviere, C., Pujos, M. The use of medicaments in space-Therapeutic measures and potential impact of pharmacokinetics due to weightlessness. ESA Journal, 1833-50, 1994. 3. Lesne, M. Influence de la decompensation cardiaque sur les parametres pharmacocinetiques des medicaments. SEMPER, 11:26-29, 1988. 4. Labaune. J.P. Pharmacocinbique. Principes Fondamentau. Masson, Pans. 1984. 5. Charles, J.B., Lathers, C.M. Cardiovascular adaptation to spaceflight. Journal of Clinical Pharmacology, 31:101&I 023, 1991. 6. Lathers, C.M.,Charles, J.B., Elton, K.F., Holt,T.A., Mukai,C.. Bennett, B.S..Bungo, M.W. Acute haemodynamic responses to weightlessness in humans. Journal of Clinical Pharmacology, 31:615-627, 1991. 7. Lathers, C.M., Charles, J.B., Bungo, M.W. Pharmacology in space. Part 1 Influence of adaptative changes on pharmacokinetics. Trends in Pharmacological Science, 10: 193-200, 1989. 8. Leach, C.S., Cintron, N.M., Krauhs, J.M. Metabolic changes observed in astronauts. Journal of Clinical Pharmacology, 31:921-927, 1991. 9. Leach, C.S., Inners, D.L., Charles, J.B. Changes in total body water during space flight. Journal ofCIinical Pharmacology, 31:lOOl-1006, 1991. 10. Bagian, J.P. First intramuscular administration in the U.S. space program. Journal of Clinical Pharmacology, 31:920, 1991. 11. Schwinghammer, T.L., Juhl, R.P. Comparison of the bioavailability of oral, rectal and intramuscular promethazine. Biopharmaceuticsand Drug Disposition, 5:185-194, 1984. 12. Backon, J., Hoffman, A. The lateral decubitus position may affect gastric emptying through an autonomic mechanism: the skin pressure vegetative reflex. British Journal of Clinical Pharmacology, 32: 138, 199 1.
Pharmacology in Space: Pharmacokinetics
121
13. Amidon, G.L., Debrincat, G.A., Najib, N. Effects ofgravity on gastric emptying, intestinal transit, and drug absorption. Journal of Clinical Pharmacology, 31:96W73, 1991. 14. Neuvonen, P.J. Interactions with absorption of tetracyclines. Drugs, 11:45, 1976. 15. Stockley, I.H. Drug Interactions.A Source BookofDrug Interactions, Their Mechanisms. Clinical Importance and Management. Blackwell, London, 2nd ed., 199 1. 16. Rowland, M., Tozer, T.N. ClinicalPharmacokinetics. ConceplsandApplications. Lea and Febiger, Philadelphia, 2nd ed., 1989. 17. Moore, T.P., Thornton, W.E. Inflight and postflight fluid shifts measured by legs volume changes. In: Results of the lije sciences DSOS conducted about the Space Shuttle 1981-1986 (NASA Editorial Review Board), pp. 59-65. NASA TM-58-280, NASA, Washington, D.C., 1987. 18. Mulvagh, S.L., Charles, J.B., Riddle, J.M., Rehbein, T.L., Bungo, M.W. Echocardiographic evaluation of the cardiovascular effects of short duration spaceflight. Journal of Clinical Pharmacology, 31:102&1026, 1991. 19. Iversen, P.O., Standa, M.. Nicolaysen. G. Marked regional heterogeneity in blood flow within a single skeletal muscle at rest and during exercise hyperaemia in the rabbit. Acta PhysiologiaScandinavica. 136:17-28, 1989. 20. Ylitalo, P. Effect of exercise on pharmacokinetics. Annals of Medicine, 23:28%294, 1991. 21. Winter, M.E., Tozer, T., Phenytoin. In: AppliedPharmacokinetics (W.G. Evans, J.J. Schentag, W.J. Jusko, Eds.), pp. 493-539.2nd ed., Applied Therapeutics, Spokane, WA, 1986. 22. Wilkinson, G.R.. Shand, D.G. A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics, 18:377-390, 1975. 23. Putcha, L. Cintron, N.M., Vanderploeg, J.M.. Chen, Y., Habis, J., Adler, J. Effect ofantiorthostatic bed rest on hepatic blood flow in man. Aviation Space EnvironmentalMedicine.59:306-308,1980. 24. Kates, R.E., Harapat, S.R., Keefe. D.L., Goldwater, D., Harrison, D.C. Influence of prolonged recumbency on drug disposition. Clinical Pharmacology and Therapeutics,28:624428, 1980. 25. Arbeille, P., Gauquelin, G., Pottier, J.M., Pourcelot, L., Giiell. A,, Gharib, C. Results of a 4-week head-down tilt with and without LBNP countermeasure: I1 Cardiac and peripheral hemodynamicscomparison with a 25 day spaceflight. Aviation Space Environmental Medicine, 63:%13, 1992. 26. Saivin, S., Pay-Le Traon, A,, Cornac, A,, Guell, A,, Houin, G. Impact of a four-day-head-down tilt (-6")on LidocaYne pharmacokinetics used as probe to evaluate hepatic blood flow. Journal of Clinical Pharmacology, 35697-704, 1995; erratum 351059, 1995.