implications of chronopharmacokinetics for drug delivery: antiasthmatics, h2-blockers and...

Advanced Drug Delivery Reviews, 6 (1991) 83--100 83 Elsevier

ADR 00077

Implications of chronopharmacokinetics for drug delivery" antiasthmatics, H2-blockers and

cardiovascular active drugs Bj6rn Lemmer

Zentrum der Pharmakologie, J. W. Goethe-Universitiit, Frankfurt am Main, Germany

(Received November 8, 1990) (Accepted November 21, 1990)

Key words: Angina pectoris; Asthma; Chronopharmacokinetics; H2-blocker; Hypertension; Nifedipine; Oral nitrate; Peptic ulcer; Propranolol; Terbutaline; Theophylline

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

II. Chronopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Antiasthmatic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Peptic ulcer disease and H2-blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Cardiovascular active drugs; 13-blockers, calcium-channel blockers and oral nitrates

III. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83

84

87 88 90 95

98

99

Summary

Circadian rhythms in the functions of the body are well established. Also the symptoms and onset of diseases are not randomly distributed within 24 h of a day (e.g., coronary infarction, angina pectoris and asthmatic attacks, peptic ulcer per- forations). It is, therefore, not surprising that also the effects and/or pharmacoki-

Abbreviations: AUC, area under the concentration-time curve; ACE, angiotensin-converting enzyme; FEV, forced expiratory volume; GI, gastrointestinal; IS, isosorbide; ISDN, isosorbidedinitrate; MN, mononitrate.

Correspondence: B. Lemmer, Zentrum der Pharmakologie, J.W. Goethe-Universit~it, Theodor-Stern- Kai 7, W-6000 Frankfurt am Main 70, Germany.

0169-409X/91/$03.50 © 1991 Elsevier Science Publishers B.V.

84 B. LEMMER

netics of drugs can display significant daily variations. Recent data on mainly the chronopharmacokinetics of antiasthmatics, Hz-blockers, and cardiovascular active drugs (propranolol, organic nitrates, nifedipine) are described as representative examples. These data demonstrate that biological rhythms have to be taken into account when evaluating drug-delivery systems, galenic formulations and pharmacokinetics as a basis for drug treatment.

I. Introduction

It is a common paradigm in clinical pharmacology that pharmacokinetic parameters are considered not to be influenced by the time of day at which a given drug is administered. Moreover, concerning drug concentration profiles “the flatter the better” is also a common aim in drug targeting. However, an increasing number of recently published studies convincingly gave evidence that these para- digms cannot be maintained any longer. It is now well established that nearly all functions of the body, including those influencing pharmacokinetic parameters, display significant daily variations (for review see Refs. l-3). Circadian (‘circa diem’ is Latin for: about 24 hours [4]), i.e., endogenously driven rhythms or 24-h or daily rhythms in heart rate, body temperature and blood pressure have already been described at the end of the 18th and in the 19th century [5-91. Though the circadian rhythm in plasma cortisol is the most well-known rhythm, numerous studies in man and in experimental animal have provided convincing evidence for the exist- ence of such rhythms not only in the rhythms already mentioned, but also in blood flow, stroke volume, peripheral resistance, parameters of ECG recordings, in the

4.00

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= Asthmatics

iz LL

1.00 1 I I 1 1 8 i6. 24 8 h

Time of day

Fig. 1. Circadian rhythm in the forced expiratory volume (FEV,) in healthy controls and asthmatic patients (redrawn according to Ref. 10).

CHRONOPHARMACOKINETICS AND DRUG DELIVERY 85

12-

F-'I ¢.-

(3" G, 6

¥

0 24

Peptic u lcer

°

IT ~ /I / ? Con t ro ls

' ' h

Clock hour

Fig. 2. Circadian rhythm in gastric acidity (H +) in 14 healthy volunteers (controls) and 21 patients with active peptic ulcer disease (redrawn according to Ref. 14).

plasma concentrations of hormones such as cortisol, melatonin, insulin, prolactin, noradrenaline, renin, angiotensin, aldosterone, in atrial natriuretic hormone and plasma cAMP concentration, in blood viscosity, aggregability and fibrinolytic activity, in the plasma concentrations of glucose, electrolytes, plasma proteins, enzymes, in the number of circulating red and white blood cells and blood platelets, etc. Moreover , various functions of the lung (minute volume, peak flow, FEVI

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Fig. 3. Daily variation in the occurrence of 1631 attacks of dyspnea in 3129 untreated, mainly asthmatic patients (redrawn according to Ref. 16).

86 B. LEMMER

ANGINA PECTORIS

ST-Segment Elevahon

~'~° ;,..; ........... \ /""

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CEREBRAL INFARCTION

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Clock hour

MYOCARDIAL INFARCTION

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Clock hour

95-

85-

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6 5 -

~ 55-

o t,5-

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n=778

; ,'s ~, ' Clock hour

17o DEATH RATE

150 (ischemic heart disease) 125-1

130 • ~ o~ ¶ n=1251

70 ..r 95 1 50 85 • / o . •

75 L , , , , , , , , , , , , ,

0-2 6-8 12-14 18-20 0-2 Clock hour

Fig. 4. Summary of circadian-stage-dependent path•physiological findings in cardiovascular diseases. Angina pectoris: ST-segment elevation in 25 patients with variant angina [17]; angina attacks find ECG- abnormalities such as ST-segment elevation, T-wave pseudonormalization in 13 patients with variant angina [18]; ST-segment depression and painful episodes (n=165) during ambulatory monitoring in patients subsequently undergoing coronary angiography [19]. Myocardial infarction: onset evaluated by the MB-creatinase method in 703 patients [20]. Cerebral infarction: evaluated in 778 male and female patients [21]. Death rate: evaluated in 1251 patients on ischemic heart disease [22]. Figures were redrawn

according to the references mentioned (from Ref. 13).

(Fig. 1), dynamic compl iance ) , o f the liver metabo l i sm, b lood f low, first pass effect) and o f the k idneys (g lomerular fi ltration, renal p lasma f low, p H , urine vol- u m e , e lectro lyte excret ion) vary with t ime o f day (for review see Refs . 1-3 , 12 and 13). A l s o gastric acid secret ion exhibits a p r o n o u n c e d circadian variat ion with peak values in the late a f t ernoon in normal subjects as well as in patients suffering from pept ic ulcer (Fig. 2 [14]). Finally, also the onset and s y m p t o m s of certain diseases do not occur at r a n d o m within 24 h of a day: already in 1698 John Floyer [15] reported that a s thma attacks are m o r e frequent at nightly hours than at other t imes of day, an observat ion which has nicely been c o n f i r m e d in m o d e r n ep idemio log i c studies in asthmatic patients (Fig. 3; [11,16]). Similarly, the occurrence o f coronary


B R A I N

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Fig. 5. 24-Hour variations in the t~-receptor-adenylate cyclase-cAMP-phosphodiesterase system in rat forebrain. Shown is a number of specific binding sites (Bmax) and dissociation constant (Kd) of [3H]DHA, the endogenous cAMP concentration, and the activities of the adenylate cyclase (AC) and

low affinity phosphodiesterase (PDE) (from Ref. 23).

infarction as well as of angina pectoris attacks and of pathologic ECG-recordings is unevenly distributed over the 24-h span of a day as shown in Fig. 4 [17-22].

In animal experiments significant 24-h rhythms have been demonstrated down to the cellular and subcellular level of, e.g., various neurotransmitter receptors and enzyme activities [23-25]. The rhythmic variations in the 13-adrenergic-mediated signal transmission (i.e., [3-receptor-adenylate cyclase-cAMP-phosphodiesterase system) in the rat brain (Fig. 5) or heart are shown to give an example out of the numerous data published (for review see Refs. 3 and 25). It is interesting to note that the rhythms in basal and in drug-stimulated adenylate cyclase activity in rat cardiac tissue in vitro (!) [24,26] are abolished with increasing age (Fig. 6; [26]), indicating that increased age may be associated with reduced circadian reactivity.

II. Chronopharmacology

Based on the chronobiologic and chronopathologic findings described above it is

88

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Fig. 6. Basal (left) and max imum of in vitro forskolin-stimulated (right) adenylate cyclase activity in rat heart ventricles of rats of different ages (I, 7 weeks; II, 4 months; III, more than 10 months) killed at eight different t imes of day. Cosinor analysis (12-h rhythm) was only significant in group I under both

conditions (from Ref. 26).

!

19 h

not surprising that the pharmacokinetics and/or the effects of drugs may also not be constant within 24 h of a day. This has been convincingly demonstrated in experimental animals as well as in clinical studies. In Tables I and II drugs are listed for which daily variations in their pharmacokinetics (Table I) or in the drugs' effects (Table II) have been reported in man. These findings must have also implications for drug targeting including the problems involved in drug delivery.

In this review only some representative findings in three different areas of drug treatment will be described to demonstrate that the rhythmic circadian organisation of the body can influence parameters pertinent for the pharmacokinetics as well as the effects and/or side effects of drugs bearing potential importance for drug targeting.

H.1. Antiasthmatic drugs Since nocturnal asthma is a common event in asthmatic disease [10,11,16] it is

not surprising that antiasthmatic drugs have also been studied in relation to time of day [11,27]. Theophylline was one of the first drugs for which daily variations in its pharmacokinetics were reported with peak drug concentrations (Cmax) being higher and time-to-peak concentration (tmax) being shorter after morning than after evening application [28]. Up to now more than 49 studies were published [27] covering different theophylline preparations in different galenic formulations. These data in general demonstrated that Cmax was lower and/or tmax was longer after evening than

CHRONOPI--IARMACOKINETICS AND DRUG DELIVERY 89

TABLE I

Drugs for which daily variations in their pharmacokinetics were reported in clinical studies. From Ref. 12.

Chronopharmacokinetics Chronopharmacokinetics

Cardiovascular active drugs Antiasthmatic drugs [~-Blockers Aminophylline

Propranolol Terbutaline Prednisolone

Calcium-channel blockers Diltiazem NSAIDs, local anesthetics Nifedipine Acetylsalicylic acid Verapamil Indomethacine

Ketoprofen Organic nitrates Phenacetin

Isosorbide-dinitrate Lidocaine Isosorbide-5-mononitrate

Anticancer drugs Digoxin Methyldigoxin Cisplatin Potassium chloride Doxorubicine Dipyridamol Cyclosporine

Psychotropic drugs Benzodiazepines

Diazepam Midazolam

Melatonin Hexobarbitone Amitriptyline Lithium Haloperidol Carbamazepine Diphenylhydantoine Valproic acid

Lorazepam Temazepam

Nortriptyline

Miscellaneous Ethanol Mequitazine

Antibiotics AmpiciUin Gentamycin Griseofulvin Sulphasymazine Sulphisomidine

GI-tract Cimetidine

Theophylline

Paracetamol Bupivacaine

5-Fluorouracil

after morning application of theophylline, supporting the early data published by Scott et al. [28]. Moreover, recent data indicate th:at theophylline might be dosed higher during the night than during daytime hours - or even a single evening dose might be used - in order to overcome the nocturnal decrease in pulmonary function adequately (Fig. 7 [27,29]). In contrast to the general belief concerning drug concentration curves ("the flatter the better") it seems, therefore, to be advantageous to accept greater fluctuations in drug concentrations throughout 24 hours of a day (Fig. 7) in order to achieve the therapeutic goal better. It is interesting to note that in 1989 for the first time a pharmaceutical company was granted permission from the Food and Drug Administration to market a theophylline tablet product for once-daily evening administration for nocturnal asthma [30].

In the treatment of asthmatic patients 132-sympathomimetic drugs are also of remedies' first choice. Recently, data were published indicating that not only the pharmacokinetics of the 132-sympathomimetic terbutaline but also its effects on

90

TABLE II

Drugs for which daily variations in their effects were reported in clinical studies From Ref. 12

B. LEMMER

Chronopharmacodynamics Chronopharmacodynamics

Cardiovascular active drugs Antiasthmatic drugs 13-Blockers Theophylline

Acebutolol Metoprolol Orciprenaline Atenolol Nadolol Terbutaline Bevantolol Oxprenolol Metacholine Bopindolol Pindolol Methylprednisolone Labetolol Propranolol Dexamethasone Mepindolol Sotalol Terbutaline + Budesonide

Calcium channel blockers Psychotropic drug Amlodipine Nitrendipine Diazepam Nifedipine Verapamil Haloperidol Nisoldipine Phenylpropanolamine

ACE inhibitors H~-Antihistamines Captopril Enalapril Clemastine

Cyproheptadine Diuretics Mequitazine

Hydrochlorothiazide Indapamide Piretanide NSAIDS, general and local Xipamide anesthetics and opiods

Acetylsalicylic acid Flurbiprofen Ketoprofen Paracetamol Tenoxicam Carticaine Mepivacaine Morphine Halothane

Organic nitrates Glyceryl-trinitrate Isosorbide-dinitrate Isosorbide-5-mononitrate

Others Clonidine Prazosin Potassium chloride

Aminophylline Isoprenaline Adrenaline

Terfenadine

Indomethacin Metamizole Piroxicam

Lidocaine

Endocrinology/gastroenterology Anticancer drugs Prednisone ACTH

Cisplatin Doxorubicin Methylprednisolone THP FUDR Insulin Tolbutamide Combinations Glucose

Bezafibrate Clofibrate Miscellaneous

Tuberculine H2-Blockers Ethanol Cimetidine Famotidine Bright light Nizatidine Ranitidine Placebo Roxatidine

p e a k e x p i r a t o r y f low were c i rcad ian p h a s e - d e p e n d e n t [31-33]. Fig. 8 d e m o n s t r a t e s tha t a f te r a s even -days t r e a t m e n t wi th ora l t e rbu ta l ine (7.5 mg at 07.30 h and at 19.30 h) Cmax was higher af ter morn ing than even ing drug app l ica t ion with tmax be ing 3.5 h and 6.2 h, respec t ive ly , thus r e sembl ing the dai ly var ia t ions o b s e r v e d


20- Ol

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200'

100

Theo: 20h

"~.-i " l / "

T T ' T . T > ~ , I / L / ~

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Fig. 7. Serum theophylline concentrations and drug effects on peak flow after theophylline dosing bid at 08.00 h and 20.00 h or after single dosing at 20.00 h, respectively (redrawn according to Ref. 29).

~ Terbutoline

t ICl I0~' "-" -",..,.,.~..,_,_,

• 0 1 . . . . ' ~ 0 12 24 36 48 60h

Fig. 8. Terbutaline plasma concentrations after a 7-days treatment with oral terbutaline (7.5 mg bid at 07.30 h and 19.30 h, arrows) (redrawn according to Ref. 31).

with theophylline. A further study with oral terbutaline indicated [32,33] that dou- bling the dose in the evening, i.e., an unequal dosing during 24 h, can better control the nocturnal fall in peak flow (Fig. 9). These studies do not only give evidence for daily variations in the pharmacokinetics and the effects of oral terbutaline but also point out that the dose-response relationship of a drug can be circadian phase- dependent .

In conclusion, the chronopharmacologic data indicate that antiasthmatic drugs such as theophylline and 13-sympathomimetics may/should be dosed higher in the evening than during daytime when asthma is predominantly nocturnal [27,29].

H.2. Peptic ulcer disease and H2-blockers This group of drugs is now the first choice in the treatment of peptic ulcer dis-

ease. Already 58 years ago Henning and Norpoth [34] reported on daily variation in gastric secretion and acidity. In 1970 Moore and Englert [14] first described the

92 B. LEMMER

E

n.,

b~ Q..

500

400

300 -

200 -

Terbutaline

/--T'T--T\TjT Con t ro l

16 24 h

C l o c k h o u r

Fig. 9. Effect of 1-week treatment with terbutaline in an unequal dosing (5 mg at 08.00 h, 10 mg at 20.00 h, arrows) on peak flow of patients suffering from chronic bronchoconstriction (redrawn according to

Ref. 32).

"17 Q.

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Placebo

8~ 1'2 18 2'4 6 h

Clock hour

Fig. 10. Effect of constant infusions of the H2-blocker ranitidine on gastric pH in man (redrawn according to Ref. 35).

circadian rhythm in gastric acid secretion in man (see Fig. 2). This chronobiologic finding unanimously led to the recommendation that H2-blockers (ranitidine, cimetidine, famotidine, roxatidine, nizatidine) should be taken once a day in the afternoon when acid secretion is increasing, independently whether the compounds have a short or a long half-life. Thus, chronopharmacology contributed to improve drug treatment as well as the patient's compliance in the treatment of peptic ulcer disease. In addition, it has quite recently been shown [35,36] that a constant infusion of ranitidine over a period of 24 h does n o t lead to a constant effect: the in- crease in gastric pH by ranitidine was less during the nightly than during the daYtime hours of drug infusion (Fig. 10), indicating that there might be a partial nocturnal resistance to H2-receptor blockade [35,36]. This interesting finding calls not only for further investigations, but could also indicate that drugs with a different


l i I \ 'odministrotion : o- ...o morning e ~ e evemng

2

o 5 10 Time. h

Fig. 11. Chronopharmacokinetics of oral cimetidine (400 rag) applied either at 08.00 h or at 20.00 h (redrawn according to Ref. 37).

mechanism of action might be added to drug treatment with H2-blockers during the nightly hours. Quite recently, daily variations in the pharmacokinetics of the H2- blocker cimetidine were reported after acute oral application [37]. Fig. 11 shows that Cmax was greater and tmax was shorter after morning than after evening dosing of cimetidine [37].

H.3. Cardiovascular active drugs: E-blockers, calcium-channel blockers and oral nitrates

The cardiovascular system also displays pronounced daily variations in its functions as well as in its hormonal and biochemical regulatory mechanisms [3,13,25,38,39]. Nearly all groups of antihypertensive and antianginal drugs were shown to exert a circadian phase dependency in their effects (see Table II). Con- cerning drug treatment of hypertensive patients, [3-blockers and calcium-channel blockers, in general, reduce high blood pressure more pronouncedly during the day than during nightly hours (for review see Refs. 38 and 39). Since it was possible that daily variations in the drugs' pharmacokinetics could contribute to the daily variation in the cardiovascular effects of these drugs, we investigated simul- taneously the pharmacokinetics and the cardiovascular effects of propranolol [40] and of nifedipine [13,41,42] on heart rate and blood pressure in healthy volunteers after drug dosing at different times of the day. In the propranolol study significant daily variations in the pharmacokinetics of oral propranolol were found: the pharmacokinetic parameterscalculated are compiled in Table III, demonstrating that

94 B. LEMMER

TABLE Ill

Pharmacokinetic parameters of (-)-propranolol and effects on heart rate after oral dosing of 80 mg racemic propranolol to healthy subjects at four different times of day as indicated Data are from Ref. 40.

Time of pro- Pharmacokinetics Hemodynamics pranolol (heart rate)

application Cmax /max AUC tl/2 ~ Cmax Emax Tmax (ng/ml) (h) (ng.mi-l.h-l)(h) tmax (beats per (h)

(ng.ml-l.h-l) min)

08.00h 3 8 . 6 - 11.2 2.5-+0.5 169---47 3.3-+0.4 17.9-+6.4 16.0---2.4 2.3-+0.6

14.00 h 20.0 --- 6.5 3.5 -+ 0.5 106 _+ 30 4.2 +- 0.5 7.5 +- 3.9 11.7 -+ 1.8 4.5 --- 1.0

20.00h 26.2---5.3 3.0-+0.6 140-+23 4.9-+0.2 10.6-+3.7 16.3-+ 1.5 6 . 5 - 1.5

02.00 h 18.4 --- 4.4" 3.5 --- 1.0 92 - 22 4.4 --- 0.6"" 7.1 -+ 2.4" 15.3 -+ 4.6 7.0 -+- 1.0 °

ANOVA: "P <0.05; "'P <0.01.

h i g h e s t Cmax, shortest tmax and tl/2 values were found after morning dosing at 08.00 h. Interestingly, the stereo-specific metabolism of propranolol was not circadian phase-dependent [40]. Fig. 12 demonstrates that the changes in heart rate in

40

30

5-

20

I0

- 4

- 8

.E - 12

-20

-2/ . I I l ''i 10 liA 24 2o i 6

T ime of d a y (h)

2 ? 12

Fig. 12. Circadian-phase dependency in the plasma concentrations of ( - ) - (closed circles) and (+)-propranolol (open circles) and of heart rate as % of circadian controls after oral intake of 80 mg racemic

propranolol by healthy volunteers either at 08.00, 14.00, 20.00 or 02.00 h local time (from Ref. 40).


relation to the respective circadian control values (hemodynamic functions were always measured in the sitting position) were also markedly different depending on the time of propranolol ingestion: after administration of propranolol at 02.00 h the heart rate was only slightly affected within the first 6 h after drug intake. However, 2 h later, at the onset of the activity span when sympathetic tone was increasing again (as demonstrated by the rhythm in plasma cAMP [42]), the heart-rate-lowering effect was pronounced again and about equally marked as when found after drug application at 08.00 h (Fig. 12). Thus, peak drug effects coincided with peak drug concentrations only after propranolol intake at 08.00 h and 14.00 h, and were delayed after propranolol dosing at 20.00 h and at 02.00 h (Fig. 12, Table III), indicating a circadian time dependency in the dose-response relationship of proprano- 1ol as well. Furthermore, these data clearly demonstrate that the chronopharmacokinetics of propranolol cannot mainly be responsible for the daily variations in the drug's hemodynamic effects [40], but that the daily rhythm in sympathetic tone is of utmost importance for the degree in 13-receptor blockade.

Recently, we were also able to demonstrate significant daily variations in the pharmacokinetics of an immediate-release preparation of nifedipine in healthy subjects [13,41,42]. In this study nifedipine was applied to healthy subjects at a dose of 10 mg either at 08.00 or at 19.00 h, respectively. The pharmacokinetic analysis revealed that not only tmax was significantly longer after evening than morning application (37.5 vs. 22.5 min), but that also Cmax (45.7 vs. 82.0 ng/ml), AUC (85 vs. 130 ng.ml-l.h -1) and drug absorption (Cm~x/tmax; 1.5 vs. 4.5 ng.ml-X.h -1) were significantly greater in the morning than in the evening. Thus, a significant daily variation in the bioavailability was found with a reduction in bioavailability of about 35% in the evening. Since the ratio in the AUC of the main nitropyridine metabolite to the parent compound was not significantly different at the two time points of drug application, we assumed that the reduction in nifedipine bioavailability must mainly be due to a reduced absorption and/or an increased presystemic metabolism in the evening [13,41,42]. Only minor daily variations were found in the cardiovascular effects of this nifedipine preparation in healthy subjects [42]. Thus it turned out that also the dose-response relationship of the calcium-channel blocker nifedipine was different during daytime and during night.

In contrast to the immediate-release formulation a sustained-release formulation of nifedipine, which we recently investigated in hypertensive patients [43,44], did not exhibit significant daily variations in its pharmacokinetics nor in its cardiovascular effects on blood pressure and heart rate in these hypertensives on chronic administration [43,44], indicating that the galenic formulation can also be of importance whether or not a chronopharmacokinetic behavior can be present.

Already in 1979 Yasue et al. [45] have shown that nitroglycerine was more effec- tive when applied in the morning than in the afternoon in reducing angina attacks in Prinzmetal angina pectoris. However, no data were available on possible daily variations in the pharmacokinetics of oral nitrates. We therefore studied the pharmacokinetics and the cardiovascular effects of oral nitrates (isosorbide-dinitrate, two formulations of isosorbide-5-mononitrate; immediate release, sustained release) in healthy volunteers [13,46-49]. Whereas the chronopharmacokinetic

96 B. L E M M E R

1600 [ S - 5 - M N

( i m m e d i a t e - re{eose f o r m u l a t i o n )

1200

E

800

18.30 h

400 06.30 h

0 r - - T - - 1 - - ~

0 4 8 12 16 20 24

hours o f fe r p o. opp l i co t ion

Fig. 13. Mean plasma concentrations of an immediate-release preparation of IS-5-MN after oral drug application of 60 mg either at 06.30 h or at ]8.30 h (from Ref. 48).

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0 ' ;. ' 6 ' 1'2 ' 1'6 ' z ' o ' 2'4 '

hours af ter p.o. appl icat ion k .

Fig. 14. Plasma concentrations of a sustained-release preparation of ]S-5-MN after ora] dosing of 60 mg either at 08.00 h or at 20.00 h (from Ref. 49).


situation is complicated in the case of ISDN [46,48] due to its complex biotransfor- mation in two active metabolites, interesting results were obtained with the two IS- 5-mononitrates [46--48]: with the immediate-release preparation of IS-5-MN clear- cut daily variations were found in regard to tmax being significantly shorter after morning (0.9---0.3 h) than after evening (2.1---0.4 h) application (Fig. 13). Most interestingly, time-to-peak drug effects in decreasing blood pressure and reflexly increasing heart rate coincided with tmax in pharmacokinetics in the morning, but were in advance by about 1 h in the evening. No daily variations were observed in the pharmacokinetics of the sustained-release formulation of IS-5-MN (Fig. 14; [46,47,49]). However, peak drug effects in lowering blood pressure and increasing heart rate again coincided with tmax in the drug's pharmacokinetics (around 5 h) but occurred about 2 h earlier after drug application in the evening. This again pointed to daily variations in the dose-response relationship of drugs, as already mentioned before, for propranolol and nifedipine. In addition, the data obtained with the two different formulations of IS-5-MN indicate that again the kind of drug formulation may be of importance whether or not chronokinetics can be observed.

Ill . Conclusion

In conclusion, the chronopharmacologic observations made with different drugs in healthy subjects as well as in diseased patients clearly indicate that the pharmacokinetics and/or the drug effects can be dependent on the time of day at which the drug is applied as well as on the circadian variation of the functions of the living organism. The delay in tm~x observed with different drugs (theophylline, terbutaline, cimetidine, propranolol, nitrates, nifedipine) after evening in comparison to morning application indicates that drug absorption can be circadian phase-dependent. Several mechanisms may be involved; firstly, a delayed gastric emptying time for solids in the evening was described [50]; however, of greater importance may be that the gastrointestinal and hepatic perfusion may change with time of day, thereby modifying the velocity of drug absorption. Evidence for daily variations in the perfusion of the gastrointestinal tract has been shown only in night-active rats in which organ perfusion was greater in the animals' activity period during darkness [51]. No such data are available in man; however, a higher cardiac output during daytime than during night is well known [52], which could contribute to a more rapid drug absorption in the morning hours.

Though a definite explanation for the chronopharmacokinetics described is not at hand, these data call for a reevaluation of the conventional thinking about pharmacokinetic processes and about problems of drug delivery from defined formulations. In addition, it is of importance to keep in mind that whether or not daily variations in the pharmacokinetics of a drug were found (e.g., IS-5-MN, nifedipine) the degree in the drugs' effects was always dependent on the time of day, even after continuous drug infusion (e.g., ranitidine). Thus, the conventional pharmacokinetic paradigm concerning drug concentration profiles "the flatter the better" may not be what the organism synchronized in time may need. There is convincing evidence that all creatures living on a planet rotating with a period of about 24 h

98 B. LEMMER

are synchronized in t ime allowing a be t te r adapta t ion to changing e nv i r onme n t a l condi t ions . This biological ent i ty has to be t aken into account even when using drugs to in f luence funct ions of the body of heal thy volunteers or of diseased pat ients . Thus , ch ronopharmaco logy is also a challenge in drug target ing including the d e v e l o p m e n t of in te l l igent drug delivery systems.

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