Recent advances in chronopharmacokinetics: methodological problems

Life Sciences, Vol. Printed in the USA

52, pp.

1809-1824

Pergamon

Press

MINIREVIEW R E C E N T ADVANCES IN C H R O N O P H A R M A C O K I N E T I C S : METHODOLOGICAL PROBLEMS Bernard Bruguerolle * and Bj6m Lemmer ** * Medical and Clinical Pharmacology Laboratory, Faculty of Medicine of Marseille, 27 blvd J.Moulin F 13385 Marseille Cedex 5 France ** Center of Pharmacology, J.W. Goethe-University, Theodor-Stem-Kai 7 D-6000 Frankfurt/M 70 Germany (Received

in final

form March 25,

1993)

Summary Chronopharmacokinetics deals with the study of the temporal changes in absorption, distribution, metabolism and elimination and thus takes into account the influence of time of administration on these different steps. In the last decade, numerous studies have been devoted to chronokinetics: recent advances will be reviewed in the first part. As representative examples, the main chronokinetic changes of anaesthetics, cardiovascular active drugs and antiinflammatory drugs in men are listed. Temporal changes can be involved at each step of the sequence of pharmacokinetic processes: temporal variations in drug absorption from the gastro-intestinal tract, in plasma protein binding and drug distribution, in drug metabolism ( temporal variations in enzyme activity, hepatic blood flow ) and in renal drug excretion may play a role. Thus, the time of administration of a drug is an important source of variation which must be taken into account in kinetic studies and particular methodological aspects of chronokinetics are needed. In a chronopharmacokinetic study many factors of variation must be controlled: factors related to the drug itself ( influence of food, galenic formulation, drug interactions), subject related-factors (age, gender, pathology, posture, exercise, synchronization) and factors related to the conditions of the administration (single or repeated dosing, constant rate delivery, route of administration). In conclusion, there are some instances in which a chronokinetic study is needed: 1) when possible daily variations in pharmacokinetics may be responsible for time dependent variations in drug effects, 2) when drugs have a narrow therapeutic range, 3) when symptoms of a disease are clearly circadian phase-dependent ( e.g. nocturnal asthma, angina pectoris, myocardial infarction, ulcer disease) 4) when drug plasma concentrations are well correlated to the therapeutic effect in case the latter is circadian phase-dependent. Variables influencing pharmacokinetics such as fasting, meals and meal times, galenic formulation, posture, activity-rest, have to be controlled according to the aim of the investigation. The main aim of chronokinetic studies is to control the time of administration which among others, can be responsible for variations of drug kinetics but also may explain chronopharmacological effects observed with certain drugs.

Copyright

0024-3205/93 $6.00 + .00 © 1993 Pergamon Press Ltd All rights reserved.

1810

Advances

in C h r o n o p h a r m a c o k i n e t i c s

Vol.

52, No.

23,

1993

Chronobiology makes it necessary to reevaluate numerous data taking into account the sampling time. Since an organism has a temporal structure which is composed by a multiplicity of biological rhythms, the effect and the fate of a drug may depend on its time o f administration. Chronopharmacokinetics concern the study of the temporal changes in drug absorption, distribution, metabolism and elimination and thus the influence of time of administration on these different steps. Chronokinetics have been reported in animals as well as in man as reviewed by Lemmer (1), Reinberg and Smolensky (2) Bruguerolle (3,4,5,6), Levi et al. (7), Reinberg et al. ( 8 ) and Lemmer et al. ( 9 ) . Temporal changes in kinetics of drugs may partly explain daily variations in their pharmacological effects. Thus, numerous studies have been devoted to chronokinetics in the last decade. Before concentrating on methodological aspects of chronopharmacokinetics, we would like to shortly review recent findings in chronokinetics. Recent advances in chronokinetics: state of the art

As representative examples of chronokinetic studies, tables 1, 2, and 3 summarize the main chronokinetic changes of anaesthetics, cardiovascular active drugs and antiinflammatory drugs in men. At each step of the fate ofthe drug in the organism (i.e. absorption, distribution, metabolism and elimination) temporal changes may play a role. When animal data are mentioned in this review it has to be reminded that in general the phase position of a rhythmic event in nocturnal animals such as rats and mice is opposite to that of day-active humans.

TABLE 1 Chronopharmacokinetic changes ofsome general or local anaesthetics in man (acute: acute treatment, i.p.: intraperitoneal route, p.o.: per os, C max.: maximum plasma concentration, T max.." time to reach C max., Ch plasma clearance Drugs

Dosing/route

Major observation

Refs

BUPIVACAINE

Peridural constant rate infusion during 36 h. 0.25 mg/kg/h,

Circadian variations of bupivacaine plasma level in spite of a constant rate infusion.Max. CI. at 06.30 h

10

HEXOBARBITAL

500 mg/p.o. acute

Highest Cmax and shortest Tmax at 02.00 h.

11

LIDOCAINE

0.65 mg/kg/lnj. acute

Highest area under plasma concentration curve at 15.30 h.

12

Temporal variations in drug absorption Mechanisms of drug absorption involve passive or facilitated diffusion, active transport, filtration through pores and pinocytosis. However, passive diffusion is by far the most important process. Concerning the most frequently used route of drug administration, absorption after oral drug dosing can be influenced by the physico-chemical properties of the drug, the area and the structure of the biomembrane, gastric emptying, pH and motility and gastro-intestinal blood flow. The rate and/or even the extent of drug absorption can be additionally modified by posture and food. Finally, the formulation of a drug product may have pronounced effects on drug absorption. In the light of circadian variations e.g. in gastric acid secretion and pH, motility, gastric emptying time and gastrointestinal blood flow (for review see Bruguerolle, 13; Lemmer, 14, 15, 16 ) it is not surprising that several clinical and experimental studies have reported on temporal variations of drug absorption (for review see Reinberg, 2 ; Lemmer, 17; and Lemmer et al. 9, 16, 18, 19 ).

Vol. 52, No. 23, 1993

Advances in Chronopharmacokinetics

1811

TABLE 2 Chronopharmacokinetic changes of cardiovascular drugs in man.(C max.: maximum plasma concentration, T max.: time to reach C max., T 1/2 8: elimination half-life, CI: plasma clearance, Vd: volume of distribution, AUC: area under plasma concentrations curve, acute: acute treatment, chronic: chronic treatment, i.p.: intraperitoneal route, p.o.: per os, n: number of studied subjects, trt: treatment). Drugs

Variable

Major observation

Cmax,Tmax, AUC

Cmax higher at 08.00 h.

20

Adult 06; 14; healthy men 22 acute,n=6 and 8 days trt 3 times daily, n=6

Plasma levels

Maxi bioavailabilty.at 08.00 h

21

Urinary excret.

Mini.urinary excretion 22 between 18.00 and 02.00 h.

ENALAPRIL

Adult healthy 08; 20 subjects,acute, n=8

Cmax, T max AUC metabolite

T max. highest at 20.00 h

ISOSORBIDE DINITRATE

Adult healthy men n=6

02; 08; 14; 20

Cmax,Tmax, AUC, T 1/2

ISOSORBIDE -5MONONITRATE Immediate release

Adult healthy men, acute, n=8

06.30; 18.30

C max, T max AUC, T 1/2

T max sign. shorter at 08.30 h

15, 24, 25

Sustained-release

Adult healthy men, acute n= 10

08; 20

C max, T max AUC, T 1/2

No sign.differences between 08 and 20.08 h

14,25

METHYLDIGOXIN

Adult patients n=4

04; 08 12; 16; 20

Plasma levels, AUC

Maxi AUC at 16.00 h second peak AM

26

NIFEDIPINE Immediate release

Adult healthy men, acute, n= 12

08; 19

C max, AUC highest and T max shorter at 08.00 h

9, 27, 28

No sign.differences between 08.00 and 19.00 h

18, 29

DIGOXlN DIPYRIDAMOLE

State,trt, number Elderly men acute, n = 9

Hours of administration 09; 21

Highest AUC at 02.00 h, T 1/2 longest at 02.00 h

Refs

23

15, 24

Sustained-release

Hypertensive 08; 19 men, 7 days treatment twice daily, n= 12

C max, Tmax AUC, T 1/2, Cmax/Tmax, Metabolite C max, T max AUC, T 1/2, Cmax/Tmax, Metabolite

Intravenously

Adult healthy men, n=12

Initial conc. AUC, T 1/2

No signif.differences

29

07; 08 19; 20

NITRENDIPINE

Adult 09; 21 healthy subjects acute, n= 8

Cmax.,Tmax. T 1/2 8,AUC

Cmax.higher at 09.00 h

30

NITRENDIPINE

Adult healthy 09; 20 subjects, 8 days trt. n=10

Plasma levels

No signif.differences

31

PROCAINAMIDE

Adult men and women, acute n= 8

07; 19

Cmax, Tmax T 1/2 AUC, CI

No sign.differences

32.

PROPRANOLOL

Adult subjects acute, n=4

02; 08; 14; 20

Cmax,Tmax,AUC Cmax,AUC and Cmax./ Cmax./Tmax. Tmax. highest at 08.00 h Tl/2 Tmax. and T 1/2 lowest at 08.00 h

33

VERAPAMIL sustained-release

Adult men 08; 20 angina pectoris chronic 2 weeks n= 10

C max, T max AUC, T 1/2

34

T 1/2 sign.longer during nighttime Sign.higher AUC and T max at 20.00 h

1812

Advances

in C h r o n o p h a r m a c o k i n e t i c s

Vol.

52, No. 23,

1993

TABLE 3 Chronopharmacokinetic changes of anti-inflammatory drugs in man: C max.: maximum plasma concentration, T max.: time to reach C max., T 1/2 B: elimination half-life, Ch plasma clearance, Vd: volume of distribution, AUC: area under plasma concentrations curve, acute: acute treatment, chronic: chronic treatment, i.p.: intraperitoneal route, p.o.: per os, n: number of studied subjects, trt: treatment, SR: Slow release form Drug

State, n

Hours of administration

Major findings

Refs

INDOMETHACIN

Healthy, acute, n=9

07.00,11.00,15.00, 19.00,23.00

Highest Cmax at 07.00 h-11.00 h longest T 1/2 8 at 19.00 h

35

INDOMETHACIN SR

Osteoarthritis acute, n=18

08.00,12.00,20.00

Highest Cmax at 12.00 h, highest AUC and longest T 1 / 2 8 at 20.00 h.

36 37

INDOMETHACIN SR

Elderly acute, n=10

09.00, 12.00, 21.00

Tmax higher at 21.00 h

38

KETOPROFEN

Healthy, acute, n=8

07.00,13.00,19.00 01.00

Highest Cmax and AUC at 07.00, longest T1/2 1"5at 01.00 h

39

KETOPROFEN SR

Healthy, acute, n=10

Shortest Tmax at 07.00 h

40

KETOPROFEN constant infusion

Sciatica cont. i.v. n=8

continuous i.v. during 24 h,sampling every 2 hours

Variations of plasma levels with a peak at 21.00 h

41

07.00,19.00

PRANOPROFEN

Healthy, acute, n=7

10.00, 22.00

Tmax. shorter at 10.00

30

SALICYLIC ACID

Healthy, acute, n=6

06.00,10.00,18.00, 22.00

Highest Cmax AUC and T 1/2 8 at 06.00 h

42

SALICYLIC ACID

Healthy, acute,n=6

07.00,11.00,15.00, 19.00,23.00

Urinary elim. longest at 07.00

43

SULINDAC

Healthy, 8 days trt, n=10

08.00,20.00

No signif. difference for the parent drug nore for its metabolites

44

From these studies it appears that most of the lipophilic drugs seem to be absorbed faster in man when the drug is taken in the morning as compared to evening dosing. No such data were reported for highly water-soluble drugs; as described below the galenic formulation ofa lipophilic drug is of additional importance. For some of the cardiovascular active drugs, chronopharmacokinetics were studied simultaneously with the effects on blood pressure and heart rate in order to get information about possible daily variation in the dose response relationship. In the case of propranolol (33), immediate-release isosorbide-5-mononitmte (15, 24, 25) and immediate-release nifedipine (24, 27, 29) it was interesting to note that peak concentrations did not coincide with peak drug effects when the drugs were dosed at different times of day. These data indicate that chronokinetics-at least in cardiovascular active drugs- are not mainly responsible for the circadian phase-dependency in the drugs'effects on blood pressure and heart rate. There is convincing evidence that the regulation of

Vol. 52, No. 23, 1993

Advances in Chronopharmacokinetics

1813

the circadian rhythms in blood pressure and heart rate are due to daily variations in e.g. sympathetic tone, peripheral resistance and cardiovascular sensitivity to various pressure hormones ( for review see Lemmer, 15, 17; Lemmer et al., 9 ). Thus, possible chronopharmacokinetics of cardiovascular active drugs seem to be of less importance for drug efficacy in cardiovascular diseases. Acute side effects of drugs are often correlated to initially high drug concentrations. It is plausible to assume, therefore, that such side effects may occur more pronouncedly at that time of day at which Cmax values are highest and or Tmax is shortest. At least, with an immediate-release preparation of isosorbide-5-mononitrate orthostatic hypertension was most pronounced after morning dosing at which Tmax of isosorbide-5 -mononitrate was significantly shorter than after evening dosing (9, 25

).

Temporal variations in plasma protein binding and drug distribution Many factors may influence drug protein binding: temperature, pH, physico-chemical properties of the drug, plasma concentrations of the protein involved. Each of these factors could theorically be subject to temporal variations ( for review see Bruguerolle, 13). We have reported on circadian variations for the free plasma drug levels of acidic drugs (carbamazepine,45) or basic drugs (lidocaine, 46, disopyramide, 47 ) in animals. In man only few studies have been devoted to this phenomenon. Highest plasma levels of free phenytoin or valproic acid are observed in man between 02.00 h and 06.00 h ( 48, 49 ). Lowest levels of free diazepam (50) and carbamazepine (51) were reported to occur in the morning. Finally, a circadian rhythm in cisplatin binding on plasma proteins with a maximum in the afternoon and minimum in the morning was described by Hecquet et al. (52). Bauer et al. (53) reported on circadian variations of valproic acid protein binding in young and elderly subjects: the clearance of the unbound drug was about 15% higher during the evening. All these findings may depend on temporal variations of different plasma proteins as reported by Reinberg et al. ( 5 4 ) , Bruguerolle et al. (55). From a methodological point of view, most of the previously described studies have reported temporal variations of plasma free drug levels by direct measurement in the plasma and calculating plasma protein binding by the difference with the total plasma concentration of the drug. Temporal changes are usually reported to be dependent on the amount of plasma proteins. No data were reported on possible temporal changes in the affinity of the proteins concerned: thus the latter should be assessed in future studies. Clinically significant consequences of temporal changes in drug binding are relevant only for drugs which are highly bound (more than 80 %). Thus, temporal variations in plasma drug binding may have clinical implications only for drugs characterized by a high protein binding and a small apparent volume of distribution. Some drugs may also be transported by red blood cells. Time dependency of drug binding to erythrocytes has only been reported for local anaesthetics such as lidocaine, bupivacaine, etidocaine and mepivacaine ( 56, 57, 58, 59, 60 ), indomethacin (38) and theophylline (61). The time dependency of the passage of drugs into red blood cells provides a strong argument for the existence of temporal variations in the passage of drugs through biological membranes for which red blood cells are often used as a model. Finally, daily variations in drug distribution may also depend on circadian variation in organ blood flow as concluded from studies in rat in which imipramine and its metabolite desmethylimipramine were determined in plasma and in brain after different routes and circadian times of application of imipramine (62). Temporal variations in drug metabolism Hepatic drug metabolism is generally assumed to depend on liver enzyme activity and/or hepatic blood flow. For drugs with a high extraction ratio such as lidocaine, propranolol, etc., the metabolism depends mainly on hepatic blood flow. For drugs with a low extraction ratio, on the other hand, biotransformation essentially depends on the enzymatic activity of the hepatocytes. However, for many lipophilic drugs both processes are involved in their elimination. Many factors may modify the processes of biotransformation : in this context temporal variations are of particular interest because they often were used to explain chronopharmacokinetic changes. Several chronobiological studies were devoted to the temporal changes in liver enzyme activity by direct

1814

Advances

in Chronopharmacokinetics

Vol.

52, No. 23, 1993

measurement (mainly in animals) or indirectly by determining the chronokinetics of drugs and their metabolites. Temporal variations in enzyme activity Rhythmic variations were documented in the activities of many enzymes such as in liver, kidney and brain. These findings were mainly obtained in nocturnal animals and were reviewed by Belanger (63) and by Feuers and Scheving (64), Belanger and Labrecque (65) and Cal et al. (66). These circadian changes in metabolic pathways may be responsible for many cases of variation in drug response. However, it has to be taken into consideration that the drug dosages used in these experiments were usually high. With barbiturates an interesting inverse relationship was found between the hepatic hexobarbital oxidase activity and the hexobarbital-induced sleeping time; the maximal hepatic hexobarbital oxidase activity (22.00 h) corresponds to the minimal sleep duration in rats (67, 68 ). This example is of particular interest since it underlines the temporal relationships between pharmacodynamic and pharmacokinetic parameters. No direct data on enzyme activities, however, were reported in man. Temporal variations in hepatic blood flow For drugs with a high extraction ratio (lidocaine, propranolol, etc.) the hepatic metabolism depends on the hepatic blood flow. Circadian variations in hepatic blood flow induce changes in liver perfusion and thus temporal variations in the clearance of drugs. Recently, a significant circadian rhythm in estimated hepatic blood flow was reported in supine healthy subjects being greatest at 08.00 h (16). Assuming that the indocyanine green kinetics investigated in this study at four different times of day indicate that also blood flow of the gastro-intestinal tract is greater in the morning than in the evening, these data could explain the higher C max. and/or shorter T max. found with lipophilic drugs after morning compared to evening application (14, 69 ). Klotz and Ziegler (70) reported on circadian variations in hepatic clearance o f a benzodiazepine with a high extraction ratio, midazolam, in man: the plasma clearance of this drug was reported to be higher during morning. Indirect evidence of temporal variations in drug metabolism Numerous experimental and clinical chronopharmacological studies have documented chronokinetics. Some of them have indirectly investigated temporal variations in hepatic drug metabolism capacity by demonstrating chronokinetics of drugs and their metabolites; even if a metabolite is not pharmacologically active, its measurement indicates the rate of metabolizing capacity. -Studies on conjugation: conjugation with glycuronic acid in man seems to be time dependent since the kinetics ofketoprofen and its glucuronoconjugate metabolite vary with time of day as demonstrated by Queneau et ai. (39). -Hydrolysis: decarboxylation and hydrolysis of chlorazepate leads to N-desmethyldiazepam which is also the main metabolite of diazepam; several chronokinetic studies have been carried out with this drug resulting in similar findings. In man, Naranjo et al. (50) demonstrated higher diazepam and N-desmethyldiazepam levels in the morning (09.00 h). Nakano et al. (71 ) confirmed these data in man by demonstrating higher diazepam concentrations after morning administration. -Oxidation: circadian variations in hydroxylation reactions in man were demonstrated by Nakano et al. (72) who measured nortriptyline (NT) and its major metabolite, 10-hydroxynortriptyline (10NT) the plasma concentrations of which were found to be higher after morning than evening drug intake. In contrast, oxidation of nifedipine to its main nitropyridine-metabolite does not seem to be circadian phase-dependent in man (18, 27 ). -Demethylation: studies on chronokinetics of a sustained release form of indomethacin have lead to similar results in man (36, 37 ): when given at 20.00 h indomethacin plasma levels remain much more stable than at 08.00 h or 12.00 h when plasma levels were found to be higher. Plasma O-

Vol.

52, No. 23,

1993

Advances

in Chronopharmacokinetics

1815

desmethyl indomethacin levels were found to be significantly higher after evening administration indicating daily changes in the rate of hepatic demethylation of the parent drug. Temporal variations in drug excretion Most drugs and/or their metabolites are eliminated by the renal route. Circadian rhythmicity of major renal functions i.e. glomerular filtration, renal blood flow, urinary pH, tubular resorption...have been documented in man (73, 74 ) and in the rat (75). In either species renal functions are higher in the respective activity period, i.e. during daytime in man and during nighttime in rodents. Thus the urinary excretion of many drugs may depend on these rhythmic variations (76). One of the first studies in man concerning the renal excretion of drugs was reported by Beckett and Rowland ( 7 7 ) who described the rhythmic renal excretion o f amphetamine with a maximum at the beginning of the day depending on the daily variation in urinary pH (the acrophase of urinary pH in man occurs in the morning). The physico-chemical properties of drugs are of particular importance in this field. Firstly, hydrophylic drugs are often eliminated unchanged by the kidneys. Thus, daily variation in renal elimination of these drugs are due to the above mentioned circadian rhythms in renal functions. In rats renal elimination of hydrophylic drugs such as sotalol and atenolol was significantly greater in their activity phase during nighttime (69). Secondly, renal elimination depends partially on the ionisation of drugs and thus may be modified by temporal changes in urinary pH. Related to these variations, acidic drugs such as sodium salicylate (43) and sulfasymazine (78) are excreted faster after an evening than a morning administration. In contrast, the renal excretion of sulfanilamide, another basic sulfonamide (pKa=10.5), does not vary along the 24 hour scale ( 78 ). The renal excretion of many other drugs has been shown to vary with time: as an example of the relationships between chronokinetics and chronotoxicity of drugs, studies of Levi (79) on an anticancer drug, cis-DDP, have shown an increased elimination of this drug when administered at 06.00 h in man corresponding to the time of higher nephrotoxicity of cis-DDP. Particular methodological aspects of chronokinetic studies Thus, the time of administration of a drug is an important source of variation which must be taken into account in kinetic studies. Before beginning a chronopharmacokinetic study many factors of variation must be controlled: factors related to the drug itself, to the subjects and to the conditions of administration. Drug-related factors Influence of food in chronokinetic studies As previously mentioned drug absorption can be influenced by the composition and the amount of food. Since many chronokinetic data were reported to be partly explained by temporal variations of absorption, meals must be strictly controlled in such studies: indeed, possible differences in quantitative and qualitative composition of meals as well as the unequal timing of meals in relation to drug dosing may explain in some cases a morning versus evening difference in the absorption of a drug. As in conventional kinetic studies this factor may also be suppressed by studying fasting subjects or patients. On the other hand, if the fasting interval before morning or evening drug dosing is kept constant, food effects can be ruled out. In setting up a study design one always has to decide whether to study circadian time effects (thus keeping meals, timing of meals, fasting, etc. constant) or whether one wants to approach realistic living habits of "normal" patients. Furthermore, food may modify the absorption of a drug due to its physico-chemical properties: Smolensky recently reviewed chronokinetics of theophylline (80) and has mentioned the influence of food on the temporal variations in the absorption of different formulations of theophylline. Thus we would like to underline the necessity to rigidly control feeding and fasting habits in chronokinetics studies. Finally, the aim of the study has to be made very clear !

1816

Advances

in Chronopharmacokinetics

Vol.

52, No. 23, 1993

Influence of the galenic form of the drug The possibility of a temporal variation in drug absorption may also depend on its galenic formulation. Very few studies were performed to evaluate this aspect of drug delivery. Recently Lemmer et al.( 9, 19, 24, 29 ) reported on chronokinetics of an immediate release form of isosorbide-5-mononitrate in healthy volunteers with Tmax being significantly shorter after morning than evening oral dosing. However, with a retard formulation of the same drug the authors did not find any significant difference in pharmacokinetics after morning or evening intake. Similar findings were obtained with an immediate-release and a sustained-release preparation of nifedipine (9, 18, 27, 29 ). These data clearly demonstrate that even the kind of drug formulation must be considered in a chronokinetic study before concluding on the possibility of a temporal influence. Drug interactions Obviously, as in a "usual" kinetic study the presence of additional drugs must be controlled. Drug interactions have not been studied from a chronokinetic point of view. This, however, may be an important point in modifying the degree of drug interaction differently at different times of day. Subject related-factors Age Most chronokinetic studies were conducted in healthy adults and there is very little information on the influence of age on chronokinetics. In children, Smolensky (80) reviewed chronokinetic studies on theophylline: age-related effects on theophylline disposition seem to be more pronounced in children than in adults. However, this difference may depend on the galenic form of the drug: for instance time dependent kinetic differences documented with theo-24, a once a day sustainedreleased drug, were found both in children and in adults (81 ) whereas circadian time-dependent variations were more pronounced with immediate-release preparations. In the elderly any few chronokinetic studies have been conducted as shown in table 4. Theophylline and digoxin chronokinetics for instance seem to be unchanged in the aged. Concerning indomethacin the chronokinetic pattern documented in adults was not the same as found in elderly subjects (table 4).

TABLE 4 Chronopharmacokinetics in the elderly sr: slow release form, p.o.: per os, s.d.: single dose Drug

Subjects n/gender/age

Dosage/Hours of administration

Major findings

R6fs

10 men 76 years

1000 mg p.o.s.d. 07.00-19.00 h

T 1/2 ~ higher at 21.00; Cmax, Tmax, AUC: ns

82

3 men 3women 75 years

0.5 mg p.o.s.d. 07.00-19.00 h

Cmax.higher at 07.00; Tmax,T1/28 AUC ns

20

INDOMETHACtN

10 men 74 years

75 mg s.r.p.o.s.d 09.00-12.00-21.00

T max higher at 21.00, Cmax, Tl/28, AUC ns

38

THEOPHYLLINE

7 women 1 men

225 mg s.r.p.o.s.d and rep.dos. 4d. 09.00-21.00

Tmax higher at 21.00 Cmax, AUC higher & 09.00

83

ACETAMINOPHEN

DIGOXIN

Vol. 52, NO. 23, 1993

Advances in Chronopharmacokinetics

1817

Gender In conventional as well as in chronokinetic studies mainly male subjects are enrolled. To the best of our knowledge there are no studies on gender-related differences in chronokinetic changes except for lorazepam (84): we did not find any significant differences between male and female adult subjects in lorazepam chronokinetics. In women the influence of menstrual cycle may also have implications on kinetics as reviewed by Bruguerolle (4): thus antipyrine ( 8 5 ) , carbamazepine (86), D-Xylose (87) nitrazepam (88), paracetamol (89) or phenobarbital (86) kinetics did not vary according to the stage of the cycle; the absorption of alcohol ( 9 0 ) and salicylates (91 ), however, has been shown to be slower in the midcycle. Methaqualone metabolism (92) has also been reported to be two times higher during ovulation. Phenytoin is more rapidly eliminated in epileptic women at the end of the cycle (93). Finally, we reported both in animals and in women that the kinetics of theophylline (61,94, 95 ) varied according to the phase of the menstrual cycle in nine female asthmatic patients: the maximum plasma drug concentration, the minimum mean residence time and the minimum elimination half-life were observed at mid-cycle (95). In contrast, ketoprofen kinetics does not significantly vary during the oestrus cycle (Bruguerolle and Bouvenot, 96 ). Pathology The state of the subjects or patients (healthy or illness) participating in a chronokinetic study may be an additional factor because biological rhythms can be modified during illness (chronopathology) and may thus interfere with drug's chronokinetics. For example the kinetics of diphenylhydantoin is different in epileptic women compared to healthy and vary in catamenial epileptic women according to the stage of the menstrual cycle (93). Recently, we reported (55, 97 ) alterations in the circadian time structure of plasma proteins in patients with cancer and with inflammatory disorders; such variations may modify drug protein binding and thus have kinetic implications. Again, respective studies are lacking. Posture and exercise Posture has been found to be of a great importance already in "normal" kinetic studies. Resting and activity, supine and upright position can influence kinetic factors involved such as hepatic blood flow. A 60 % difference in hepatic blood flow has been found in man between standing and recumbent positions (98). Digoxin and diphenylhydantoin kinetics e.g. were shown to depend on the posture with an increase in the total plasma diphenylhydantoin concentrations after 45 minutes of standing ( 9 9 ) . Exercise has also been shown to influence the kinetics of drugs: thus, propranolol clearance increases with exercise (100) and moderate exercise decrease the elimination half-life and the volume of distribution of atropine (101). It is, therefore, of great importance to control posture activity and exercise of volunteers or patients participating in chronokinetic studies. Depending on the aim of the respective study, these factors have either to be kept constant in order to exclude such factors or have to be taken into consideration in concluding the data. Synchronisation Obviously, as in any other chronobiological studies in animal and man the synchronization of the subjects must be controlled. In clinical studies daily changes in light and darkness can scarcely be kept constant. The hours of awakening and sleeping must and can be standardized together with meal times. We would like to point out a practical problem which may be often involved in chronokinetic studies: young healthy adults participating in such studies are often students: it is important to control and standardize their usual habits of life and the ususal synchronisation of their working habits and sleeping time in order to be representative with "normal life". On the other hand and as mentioned earlier, in order to study mainly the effect of circadian time on the kinetics of a drug, subject synchronisation including meals, meals timing and fasting hours may be different from " real life", e.g. in the propranolol study (33) the drug was ingested always one hour after a

1818

Advances

in C h r o n o p h a r m a c o k i n e t i c s

Vol.

52, No.

23,

1993

standardized meal at either of the four time points studied (02, 08, 14, 20 h clock time) in order to rule out meal-induced variations on drug absorption. Factors related to conditions of administration Single or repeated dosing and constant rate delivery of drugs Most chronokinetic studies have been carried out by comparing the kinetics of a drug taken at different time points after a single drug dosing. One can argue that such variations may disappear when repeated d o s e s are applied; some chronokinetic investigations have been carried out after chronic dosing (theophylline, diazepam, sodium valproate..etc.) and still have demonstrated significant temporal variations. It is a paradigm in pharmacokinetics that drug delivery at a constant rate results in constant drug levels. However, chronopharmacokinetics studies revealed that this paradigm does not hold true any longer. Thus, recent chronokinetic studies on anticancer agents: adriamycin (102), 5-fluorouracil, (103), vindesine (104) , antiinflammatory agents: ketoprofen ( 41 ), heparin (105 ), local anesthetics: bupivacaine (10 ) and terbutaline (106 ) have demonstrated that continuous intravenous infusion does not lead to constant plasma levels but in contrast results in large amplitude circadian changes (table 5). In man, in spite of a continuous (36 hours) constant rate infusion by peridural route, the plasma clearance of bupivacaine varied along the 24 hour scale with a maximum at 06.00 h (10). Programmable implanted pumps in contrast allow to vary the infusion rate in a sinusoidal fashion. Such findings have been applied to anticancer drugs. Levi et al. (102) for instance demonstrated that a constant delivery rate of adriamycin in patients suffering from advanced breast cancer resulted in temporal variations in adriamycin plasma concentrations.In contrast, when the same 24 hour dosage was delivered by an infusion rate varying in a sinusoidal fashion, the temporal changes in plasma concentrations followed the pump delivery pattem. Thus it was possible to modulate the circadian infusion rate in order to give more drug when it was best tolerated. Route of administration As previously mentioned, most chronokinetic studies have been carried out with drugs administered by oral route and some of them by intravenous route. In such cases the persistance of significant chronokinetic changes with the i.v. route as compared to the oral route allows to conclude that the absorption process do not interfere with chronokinetic changes. As already mentioned, animal data with imipramine after i.p. and i. v. application revealed that the volume of distribution in a target organ may be circadian phase-dependent (62). Quite recently, we compared in humans different routes of administration of nifedipine. In these studies no circadian phasedependency was found in nifedipine kinetics after i.v. injection (29) as well as after oral application of a sustained-release preparation, whereas pronounced chronokinetics were found of oral ingestion of an immediate-release nifedipine (9, 18, 27 ). These data clearly demonstrate that final conclusions on whether or not chronokinetics of a drug are present can only be drawn when all factors including route of administration and galenic formulation are controlled and taken into consideration. Surprisingly the transcutaneous passage of drugs have not yet been investigated from a chronokinetic point of view. We recently studied the influence of the hour of administration on the kinetics oflidocaine, a local anaesthetic drug, in animals and in children. Our data indicate that the lidocaine plasma levels were significantly different: higher in the evening for the children and in the morning for the rats (107). The plasma levels of local anesthetics (LA) can indicate the degree of elimination and thus may be inversely correlated to the amount of the LA applied to the skin. Theoretical problems Necessity of several time points of investigation It is obvious that possible chronokinetics are best studied and detected investigating drug application at several times of day. Limitation to two time points may miss a temporal variation. However, in

VOI. 52, No. 23, 1993

Advances in Chronopharmacokinetics

1819

clinical studies more than two time points of drug application are mostly difficult to obtain. I f only two times of administration are possible, the choice of these time points must be determined according to a preliminary experiment or according to pertinent information such as on a certain phase relation to the peak or trough time of a biological marker rhythm ( 8 ) . Practical aspects of drug treatment can be considered, too, as in the case of nocturnal asthma or primary hypertension (peak values in blood pressure during day) and secondary hypertension (peak time in blood pressure during night).

TABLE 5 Chronokinetics after intravenous infusion at constant rate

Drug

State, n

Administration/ dosage

Major findings

BUPIVACAINE

Adult patients (surgical intervention) n= 13

Continuous peridural infusion during 38 hrs 0.25 mg/kg/h

Highest plasma clearance at 06.30 h

5-FLUOROURACIL

Adult patients (bladder carcinoma) n=7

Cont.i.v. infusion during 5 days 450-966 mg/m2/day

Mean highest plasma levels at 01.00 h

KETOPROFEN

Adult patients (Sciatica), n=8

Continuous i.v.infusion during 24 h, 5mg/kg/day

Variations of plasma levels with a peak at 21.00 h

41

MIDAZOLAM

Adult healthy subjects n=5

Constant infusion for 26 hrsof 0.025 mg/kg/h preceded by a bolus of 0.05 mg/kg

Plasma levels higher during nighttime only sign.in one subj.

108

SODIUM VALPROATE

Monkeys n=4

Constant rate infusion Plasma levels and CSF fluid 75 mg/hr during 2 weeks highest during dark period (02.00-05.00 h)

TERBUTALINE

Adult asthmatic Constant rate infusion, patients 0.033 mg/kg during n=15 24 hrs preceded by a 2.94 IJg/kg bolus

Highest plasma levels at 23.00 h

106

THEOPHYLLINE

Asthmatic children, n=10

Continuous infusion during 24 hrs

No sign.temporal variation in plasma levels

109

Asthmatic patients, n=8

Continuous infusion during 36 hrs

No sign. temporal variation in plasma levels

110

Highest plasma concentrations at 12.00 h

104

VlNDESINE

Adult patients Continuous i.v. (lung carcinoma) infusion, n= 25 3 mg/m2/day during 48 hrs.

Refs 10

103

49

Predictability of a temporal kinetic variation From the results of all these investigations it is not easy to define a specific chronokinetic pattem for drugs of the same chemical group. The predictibility of the amplitude and the pattern of temporal variations in drug kinetics has been approached by several authors; Belanger et al. (111 ) have

1820

Advances

in C h r o n o p h a r m a c o k i n e t i c s

Vol.

52, No. 23,

1993

demonstrated in rats that some physico-chemical properties such as liposolubility or hydrophilicity may influence the chronokinetic pattern of a given drug. They have shown that drugs with low water solubility such as indomethacin, furosemide, phenylbutazone etc.., exhibit a circadian variation of absorption while this is not the case for water soluble drugs such as antipyrine, hydrochlorothiazide or paracetamol. In contrast, these drugs have been shown to have a timedependent clearance. Lemmer et al. (2, 67 ) have also emphasized on the importance of lipophilicity or hydrophilicity for the chronokinetics of beta adrenoceptor blocking drugs. Finally, Bruguerolle and Prat (57, 58, 59, 60) have underlined the chronokinetic differences of local anaesthetics related to their physico-chemical properties. Which protocol in chronokinetic studies ? When, Why and How ? We would like to conclude on pratical considerations by asking two questions: 1) when is it necessary to perform a chronokinetic study ? when a chronokinetic explanation is suggested to explain chronopharmacological data when using a drug with a narrow therapeutic range when using a drug whose plasma concentration is well correlated to the pharmacological or the therapeutic effect - when symptoms of the disease are clearly circadian phase-dependent as in nocturnal asthma, angina pectoris, primary or secondary hypertension and ulcer disease (for review see Lemmer, 9, 19 ). 2) how and under which conditions to conduct such a study ? .All variables as already mentioned have to be strictly controlled, including fasting times, meals, galenic formulation, posture, rest-activity etc. .When "time" is the main endpoint of research even unusual patterns of meal times, posture, etc have to be selected. .When therapeutic recommendations are endpoints of research (e.g.evening dosing instead morning dosing), "real life" conditions may be more appropriate. -

-

-

Conclusions There is no doubt that the pharmacokinetics can be significantly influenced by time of day of administration. This observation is rather new and deserves clinical implications. Moreover, chronokinetics can- but must not always- be responsible for daily variation in drug effects and/or side effects. Finally, it is well documented that symptoms and the onset of certain diseases (asthma, angina pectoris, myocardial infarction, hypertension, ulcer disease) are not randomly distributed over the 24 hour scale but predominate at certain times of day. This implies that the timing of drug treatment has to vary according to the symptoms observed. It is, therefore, of importance to rigorously control factors which are known to influence pharmacokinetic processes in chronokinetic studies. Time of day has to be regarded as an additional variable to influence the kinetics of a drag.

References 1. 2. 3. 4. 5. 6. 7.

B. LEMMER, D. Breimer and P. Speiser (eds), 49-68, Topics in pharmaceutical Sciences, Elsevier, North Holland Biomedical Press ( 1981). A. REINBERG and M.H. SMOLENSKY, Clin. Pharmacokinet. 7 401-420 (1982). B. BRUGUEROLLE, Th6rapie 38 223-235, (1983). B. BRUGUEROLLE, J. Gyn6col. Obst. Biol. Reprod. 12 825-827 (1983). B. BRUGUEROLLE, La Chronopharmacologie, Ellipses (ed.) Paris (1984). B. BRUGUEROLLE, Pathol. Biol.35 925-934 (1987). F. LEVI, B. BRUGUEROLLE and B. HECQUET, Th6rapie44 313-321 (1989).

Vol. 52, No. 23, 1993

8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

Advances

in C h r o n o p h a r m a c o k i n e t i c s

1821

A. REINBERG, F. LEVI, M. SMOLENSKY, G. LABRECQUE, M. OLLAGNIER, H. DECOUSUS and B. BRUGUEROLLE, C. Hansch (ed.) Comprehensive Medicinal chemistry 5, 279-296, Pergamon Press (1990). B. LEMMER, B. SCHEIDEL and S. BEHNE, Ann. N.Y. Acad. Sci. 618 166-181 (1991). B. BRUGUEROLLE, M. DUPONT, P. LEBRE and G. LEGRE G, Annu. Rev. Chronopharmacoi. 5 223-226 (1988). P. ALTMAYER, E. GROTERATH, P.W. LUCKER, D. MAYER, H. VON MAYERSBACH, Arzn. Forsch. Drug Res. 29 1422-1428 (1979). B.BRUGUEROLLE and R. ISNARDON, Ther. Drug Monit. 7 369-370 (1985). B. BRUGUEROLLE, Lemmer B (ed) Chronopharmacology -Cellular and Biochemical Interactions, 3-13, Dekker M New York, Basel (1989). B. LEMMER, Adv. Drug Deliv. Rev. 6 83-100 (1991). B. LEMMER, Internist32 380-388 (1991). B. LEMMER and G. NOLD, Br. J. Clin. Pharmacol. 32 627-629 (1991). B. LEMMER B, H.P. Kuemmerle, G. Hitzenberger and K.H. Spitzy (eds) Clinical pharmacology, 4 th edit, ecomed Verlagsgesellschafft, Landsberg Miinchen 11 1-14 (1988). B. LEMMER, G. NOLD and R. KAISER, Naun-Schm. Arch. Pharmacol. 343 R 125 (1991). B. LEMMER, B. SCHEIDEL, H. BLUME and H.J. BECKER, Eur. J. Ciin. Pharmacol. 40 71-75 (1991). B. BRUGUEROLLE, G. BOUVENOT, R. BARTOLIN and J. MANOLIS, Thdmpie43 251-253 (1988). A. MARKIEWlCZ, K. SEMENOWlCZ, J. KORCZYNSK and J. CZACHOWSKA. Int. J. Clin. Pharmacol. Biopharm. 17 222-224 (1979). A. MARKIEWlCZ AND K. SEMENOWlCZ K, Pol. J. Pharmacol. Pharm. 32 289-295 (1980). K. WEISSER, J. SCHLOOS, K. LEHMANN, R. DUSING, H. VETTER and E. MUTSCHLER, Eur. J. Pharmacol. 40 95-99 (1991). B. LEMMER, B. SCHEIDEL, G. STENZHORN, H. BLUME, G. LENHARD, D. GRETHER, J. RENCZES andH.J. BECKER, Zeit. Kardiol. 78 61-63 (1989). B. SCHEIDEL and B. LEMMER, Chronobiol. Intern. 8 409-419 (1991). L. CAROSELLA, P. DINARDO, R. BERNABEI, A. COCCHI AND P. CARBONIN, A. Reinberg and F. Halberg (eds) Chronopharmacology, 125-130, Pergamon Press Oxford (1979). B. LEMMER, G. NOLD, S. BEHNE, H.J. BECKER, J. LIEFHOLD and R. KAISER, Eur. J. Clin. Pharmacol. 183 521-526 (1990). B. SCHEIDEL, B. LEMMER and H. BLUME, B. Lemmer and H. Huller (eds), Clinical Pharmacolgy, 75-79, Verlag (1990). B. LEMMER, G. NOLD, S. BEHNE and R. KAISER, Chronobiol. Int. 8 485-494 (1991). A. FUJIMURA, H. KAJIYAMA,Y. KUMAGAI, H. NAKASHIMA, K. SUGIMOTO and A. EBIHARA, J. Clin. Pharmacol. 29 786-790 (1989). P. JAILLON and B. LECOCQ, Lettre Pharmacol. 3 222-225 (1989). A. FUJIMURA, K. OHASHI, K. SUGIMOTO, Y. KUMAGAI and A. EBIHARA, J. Clin. Pharmacol. 29 909-915 (1989). B. LANGNER and B. LEMMER, Eur. J. Ciin.Pharmacol. 33 619-624 (1988). C.M. JESPERSEN, M. FREDERICKSEN, J. FISHER HANSEN, N.A. KLITGAARD and C. SOERUM, Eur. J. Clin. Pharmacol. 37 613-615 (1989). J. CLENCH, A. REINBERG, Z. DZIEWANOWSKA, J. GHATA, and M. SMOLENSKY, Eur. J. Clin. Pharmacol. 20 359-369 (1981). P. GUISSOU, G. CUISINAUD, G. LLORCA, E. LEJEUNE and J. SASSARD, Eur. J. Clin. Pharmacol. 24 667-670 (1983). B. BRUGUEROLLE, C. DESNUELLE, G. JADOT, M. VALLI and P.C. ACQUAVIVA, Rev. Int. Rhum. 13 263-267 (1983). B. BRUGUEROLLE, G. BARBEAU, P. BELANGER and G. LABRECQUE, Annu. Rev. Chronopharmacol. 3 425-428 (1986).

1822

39. 40.

41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71.

Advances in Chronopharmacokinetics

Vol. 52, No. 23, 1993

P. QUENEAU, M. OLLAGNIER, H. DECOUSUS and Y. CHERRAH, Annu. Rev. Chronopharmacol. 1 353-356 (1984). A. REINBERG A, F. LEVI, Y. TOUITOU, A. LE LIBOUX, J. SIMON, A. FRYDMAN A. BICAKOVA-ROCHER and B. BRUGUEROLLE, Annu. Rev. Chronopharmacol. 3 317-320 (1986). H. DECOUSUS, M. OLLAGNIER, Y. CHERRAH, B. PERPOINT, J. HOCQUART and P. QUENEAU, Annu. Rev. Chronopharmacol. 3 321-324 (1986). A. MARKIEWICZ and K. SEMENOWlCZ, Int. J. Clin. Pharmacol. Biopharm. 17 409411 (1979). A. REINBERG, J. CLENCH, J. G H A T A , F. HALBERG, C. ABULKER, J. DUPONT andZ. ZAGULA-MALLY, C. R. Acad. Sci. (Paris) 280 1697-1700 (1975). W. C O U E T , I. INGRAND, L. MILLERIOUX, M.A. LEFEBVRE, Y. MAINGUY and J.B. FOURTILLAN, Sem. H6p. Paris 62 2677-2682 (1986). B. BRUGUEROLLE, M. VALLI, G. JADOT, L. BOUYARD and P. BOUYARD, Eur. J. DrugMetab. Pharmacokinet. 6 189-194 (1981). B. BRUGUEROLLE, G. JADOT, M. V A L L I , L. BOUYARD and P. BOUYARD, J. Pharmacol. (Paris) 13 65-76 (1982). B. BRUGUEROLLE, Chronobiol. Int. 1 267-271 (1984 ). I.H. PATEL, R. VENKATARAMANAN, R.H. LEVY, C.T. VISWANATHAN and L.M. OJEMANN, Epilepsia 23 282-290 (1982). J.S. LOCKARD, C.T. VISWANATHAN and R.H. LEVY, Life Sci. 6 1281-1285 (1985). C.A. NARANJO, E.M. SELLERS, H.G. GILES and J.G. ABEL, Br. J. Clin.Pharmacol. 9 265-272 (1980). R. RIVA, F. ALBANI, G. AMBROSETTO, M. CONTIN, P. CORTELLI, E. PERUCCA and A. BARUZZI A., Epilepsia 25 476-481 (1984). B. HECQUET, J. MEYNADIER, J. BONNETERRE and L. ADENIS, Annu. Rev. Chronopharmacol. 3 115-118 (1984). L.A. BAUER, R. DAVIS, A. WILENSKY, V. RAISYS AND R.H. LEVY, Clin. Pharmacol. Ther. 37 697-700 (1985). A. REINBERG, E. SCHULLER, N. DESLANERIE, J. CLENCH and M. HELARY, Nouv. PresseMed. 6 3819-3823 (1977). B. BRUGUEROLLE, F. LEVI, C. ARNAUD, G. BOUVENOT, M. MECHKOURI, J. VANNETZEL and Y. TOUITOU, Annu. Rev. Chronopharmacol. 3 207-210 (1986). B. BRUGUEROLLE and G. JADOT, Chronobiologia 10 295-297 (1983). B. BRUGUEROLLE and M. PRAT, J. Pharm. Pharmacol. 39 148-149 (1987). B. BRUGUEROLLE and M. PRAT, J. Pharm. Pharmacol. 40 592-594 (1988). B. BRUGUEROLLE and M. PRAT, Life Science 45 2587-2589 (1989). B. BRUGUEROLLE and M. PRAT, J. Pharm. Pharmacol. 42 201-202 (1990). B. BRUGUEROLLE, Med. Sci. Res. (Biochemistry) 15 263-264 (1987). B. LEMMERand L. HOLLE, Chronobiol. Int. 8 176-180 (1991). P.M. BELANGER, Annu. Rev. Chronopharmacoh 4 1-46 (1988). R.J. FEUERS and L.E. SCHEVING, Annu. Rev. Chronopharmacol. 4 209-254 (1988). P.M. BELANGER AND G. LABRECQUE, Lemmer B (ed) ChronopharmacologyCellular and Biochemical Interactions, B. Lemmer (ed.), 25-34, Dekker M New York Basel (1989). J.C. CAL, C. DORAIN, P. CATROUX and J. CAMBAR, B. Lemmer (ed) Chronopharmacology-Cellular and biochemical interactions, 655-681, Dekker M, NewYork, Basel (1989). V. NAIR and R. CASPER, Life Sci. 8 1291-1298 (1969). V. NAIR, L.E. Scheving et al. (eds)Chronobiology, 182, Igaku Shoin Tokyo (1974). B. LEMMER, H. WlNKLER, T. OHM and M. FINK, Naun.-Schmied. Arch. Pharmacol. 330 42-49 (1985). U. KLOTZ and G. ZIEGLER, Clin. Phamaacol. Ther. 32 107-112 (1982). S. NAKANO, H. WATANABE, K. NAGAI and N. OGAWA, Clin. Pharmacol. Ther. 36 271-277 (1984).

Vol. 52, NO. 23, 1993

Advances in Chronopharmacokinetics

1823

72. S. NAKANO and L.E. HOLLISTER, Clin. Pharmacol. Ther. 23 199-203 (1978). 73. M.G. KOOPMAN, R.T. KREDIET and L. ARISZ, Neth. J. Med. 28 416-423 (1985). 74. J.M. WATERHOUSE and D.S. MINOR, Chronopharmacology-Cellular and Biochemical Interactions, B. Lemmer(ed.), 35-50, DekkerM New YorkBasel (1989). 75. J. CAMBAR, F. LEMOIGNE and C. TOUSSAINT, Experientia 35 1607-1608 (1979). 76. B.M. JONES and M.K. JONES, Ann. N. Y. Acad. Sci. 273 576-587 (1976). 77. A.H. BECKETT and M. ROWLAND, Nature 204 1203-1204 (1964). Cellular and biochemical interactions, 15-34, Dekker M New-York, Basel (1989). 78. L. DETTLI and P. SPRING, Helv. Med. Acta4 921-926 (1966). 79. F. LEVI, Chronopharmacologie de trois agents dou(s d'activit~ anticanc#reuse chez le rat et la souris.Chronoefficacit( et chronotol(rance. PhD Thesis, Paris, (1982). 80. M.H. SMOLENSKY, B. Lemmer B (ed) Chronopharmacology-Cellular and Biochemical Interactions, 65-114, Dekker M New York Basel (1989). 81. M. SMOLENSKY, P.H. SCOTT, R.B. HARRIST, P.H. HIATT, T.K. WONG, J.C. BAENZIGER, B.J. KLANK, A. MARBELLA and A. MELTZER, Chronobiol. Intern. 4 435-448 (1987). 82. B. BRUGUEROLLE, G. BOUVENOT, R. BARTOLIN and B. POUYET, Anna. Rev. Chronopharmacol. 7 265-268 (1990). 83. A. RODGERS, K.W. WOODHOUSE and D.N. BATEMAN, Br. J. Clin. Pharmacol. 25 523-524 (1988). 84. B. BRUGUEROLLE, G. BOUVENOT, R. BARTOLIN, Annu. Rev.Chronopharmacol. 1 21-24 (1984). 85. G. KELLERMAN, M. LUYTEN-KELLERMAN, M.G. HORNING and D.M. STAFFORD, Clin. Pharmacol. Ther. 20 72-80 (1976). 86. P. BACKSTROM and P. JORPES, Acta Neurol. Scand. 58 63-71 (1979). 87. C. FISET and M. LEBEL, Clin. Pharmacol. Ther. 48 529-536 (1990). 88. R. JOCHEMSEN, M.VAN DER GRAAF, J.K. BOEIJINGA and D.D. BREIMER, Br. J. Clin. Pharmacol. 13 319-324 (1982). 89. B. WOJCICKI, B. GAWRONSKA-SZKLARZ and B. KAZIEMIER-CZYKZ, Arzn.Forsch. Drug Res. 29 350-352 (1979). 90. H.B. JONES, Philosoph. Trans Royal Soc. (London) 135 335-349 (1845). 91. S.L. MIASKEWICZ, C.A. SHIVELLY and E.S. VESELL, Ciin. Pharmacol. Ther. 31 3 0-37 (1982). 92. K. WILSON, M. ORAM, C.E. HORTH and D. BURNETT, Brit. J. Ciin. Pharmacol. 14 333-339 (1982). 93. G. SHAVIT, P. LERMAN and A. KORCSYN, Neurol. 34 959-961 (1984). 94. B. BRUGUEROLLE, Pathol. Biol. 35 181-183 (1987). 95. B. BRUGUEROLLE, M. TOUMI, F. FARAJ, D. VERVLOET and H. RAZZOUK, Eur. J. Pharmacol. 39 59-61 (1990). 96. B. BRUGUEROLLE and G. BOUVENOT, Fund. Clin. Pharmacol. 5 347-350 (1991). 97. C. FOCAN, B. BRUGUEROLLE, C. ARNAUD, F. LEVI, V. MAZY,D. FOCANHENRARD and G. BOUVENOT, Annu. Rev. Chronopharmacol. 5 21-24 (1988). 98. T.K. DANESHMEND, L. JACKSON and C.J. ROBERTS, Br. J. Clin. Pharmacol. 11 49-496 (1981). 99. F. ABALAN, G. VINCON, W. ELLISSON, M. SOUSSELIER, F. DEMOTESMAINARD, E. LACHIVER and H. ALBIN, Eur. J. Clin. Pharmacol. 38 526-527 (1990) 100. S. FRANK, S.M. SOMANI and M. KOHNLE, Eur. J. Clin.Pharmacol. 39 391-394 (1990). 101. G.H. KAMIMORI, R.C. SMALLRIDGE, D.P. REDMOND, G.L. BELENKY and H.G. FEIN, Eur. J. Clin. Pharmacol. 39 395-397 (1990). 102. F. LEVI, G. METZGER, F. BAILLEUIL, A. REINBERG and G. MATHE, Am. Ass. CancerRes. 27 175 (1986). 103. E. PETIT, G. MILANO, F. LEVI, A. THYSS, F. BAILLEUL and M. SCHNEIDER, Cancer Res. 48 1676-1679 (1988).

1824

Advances

in C h r o n o p h a r m a c o k i n e t i c s

Vol.

52, No.

23,

1993

104. C. FOCAN, L. DOALTO, V. MAZY, F. LEVI, B. BRUGUEROLLE, J.P. CANO, R. RAHMANI, and B. HECQUET, Bull. Cancer 76 909-912 (1989). 105. H. DECOUSUS, M. CROZE, F. LEVI, B. PERPOINT, J. JAUBERT, J.F. BONNADONA, A. REINBERG and P. QUENEAU, Br. Med. J. 290 341-344 0985 ). 106. F. PHILIP-JOET, B. BRUGUEROLLE, F. LAGIER, F. PIERSON, M. REYNAUD, M. LEONARDELLI M, J.P. ORLANDO, D. VERVLOET and A. ARNAUD, Respiration 59 197-200 (1992). 107. B. BRUGUEROLLE, E. GIAUFRE and M. PRAT, Chronobiol. Int. 8 277-282 (1991). 108. U. KLOTZ and I.W. REIMANN, Clin.Pharmacokinet. 9 469-474 (1984). 109. K.P. COULTHARD, D.J. BIRKETT, D.R. LINES, N. GRGURINOVICH and J.J. GRYGIEL, Eur. J. Clin.Pharmacol. 25 667-672 (1983). ll0. T. UEMATSU, F. FOLLATHand S. VOZE, Eur. J. CIin. Pharmacol. 30 309-312 (1986). 111. P.M. BELANGER, G. LABRECQUE AND F. DORE, Int. J. Chronobiol. 7 208-215 (1981).