Gastrointestinal chronopharmacology: Physiology, pharmacology and therapeutic implications

Pharmac. Ther. Vol, 54, pp. 1-15, 1992 Printed in Great Britain. All rights reserved

0163-7258/92 $15.00 © 1992 Pergamon Press Ltd

Specialist Subject Editors: P. H. REDFERNand J. WATERnOUSE

GASTROINTESTINAL CHRONOPHARMACOLOGY: PHYSIOLOGY, PHARMACOLOGY AND THERAPEUTIC IMPLICATIONS S. W. SANDERS* a n d J. G. MOOREt,J~ *University of Utah School of Medicine, Salt Lake City, UT 84148, U.S.A. tDivision of Gastroenterology, VA Medical Center, Salt Lake City, UT 84148, U.S,A. A~tract--This chapter discusses the influence of uitradian and circadian rhythms of gastrointestinal motor and secretory function on the action of orally administered drugs. Most drugs exhibit more rapid absorption in the morning compared to the evening due, in part, the circadian alterations in gastric emptying. Gastric acid secretion and gastrointestinal toxicity to oral drugs also display circadian rhythmicity. These observations provide a rationale for use or avoidance of drugs based on time-of-day dosing considerations. The chronopharmacological behavior of a drug may thus play an important role in the effectiveness of any oral medication treatment schedule. CONTENTS 1. Introduction 2. Gastrointestinal Motility 2.1. Physiology 2.2, Pharmacology 2.3. Therapeutic implications 3. Gastric Acid Secretion 3.1. Physiology 3.2. Pharmacology 3.3. Therapeutic implications 4. Gastric Mucosal Defense 4.1. Physiology 4.2. Pharmacology 4.3. Therapeutic implications 5. Seasonal Rhythms in the Incidence of Peptic Disease 6. Gastrointestinal Toxicology 7. Conclusions Acknowledgements References

1 2 2 4 6 6 6 7 9 10 10 10 11 12 12 13 13 13

1. INTRODUCTION Chronopharmacology is the study of the interactions between biological rhythms and medications. Chronopharmacokinetics refers to time-dependent differences in drug absorption, distribution, metabolism and elimination while chronopharmacodynamics refers to time-dependent changes in end-organ effects of medication. The chronokinetic and dynamic behavior of a drug are thus different; a biological rhythm may influence one or both pharmacologic aspects of a medication and the effects of medication will differ, sometimes markedly, as a function of their administration time---morning or evening, or time of the month, for example. The goal of chronotherapy is to schedule the delivery of medication in consonance with naturally occurring biological rhythms to achieve the optimum desired pharmacologic effect or to minimize toxicity. Biological rhythms may be divided into ultradian (less than ,-~20 hr), circadian (about 24 hr), or infradian (greater than ~ 28 hr) time domains. In human chronotherapy, treatment programs based upon these time domains are well known and include, for example, the control of cardiac ~Corresponding author.

2

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SANDERS a n d J. G . MOORE

arrhythmias (ultradian), night-time administration of gastric antisecretory medication for the treatment of ulcer disease (circadian), or the monthly administration of hormonal combinations for contraception (infradian). This review will focus on biological rhythms of the gastrointestinal tract that influence the pharmacokinetic, pharmacodynamic and toxicological behavior of oral medications. 2. G A S T R O I N T E S T I N A L M O T I L I T Y 2.1. PHYSIOLOGY Gastrointestinal motility patterns observed in the human alimentary tract consist of a series of coordinated electrical and contractile events that lead to aboral propulsion of foodstuffs. These sequential and rhythmic contractions of the stomach and small bowel, termed peristalsis, act to provide optimum intestinal mucosal surface exposure for the absorption of nutrients as well as orally administered drugs. The rate of transfer of drugs into the small bowel for absorption is dependent on gastric emptying, Gastric emptying, in turn, may be significantly affected by the presence or absence of food in the stomach as well as the physical composition of foodstuffs (liquid or solid). In fed subjects, gastric motor activity is dominated by peristaltic contractions. These waves, occurring in man at the frequency of 3 per min, originate as pacesetter potentials from high on the gastric greater curvature, In the presence of food or antral distension (e.g. by air), the electrical pacesetter potential converts to an action potential and muscular contraction. These contractions are responsible for the grinding of digestible solid particles to a size (less than ~ 1.0 ram) that permits passage from the antrum into the duodenum. The antrum, or distal stomach, is the major anatomical site for this function. Liquid emptying, in contrast, is under control of muscular forces generated in the proximal stomach. Liquid emptying rates are proportional to the driving gradient between the gastric fundus and duodenum. Thus, emptying of liquids and solids is under the control of separate anatomic gastric regions and display very different emptying time courses. Solid and liquid-phase emptying curves are illustrated in Fig. 1 for a mixed, solid-liquid meal (Brophy et al., 1986). The

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FIG. 1. Gastric emptying of liquid and solid foods. Note the near linear and slower emptying of solids when compared to liquids. A 300 g combined solid and liquid meal, labeled with technetium-99m-sulfur colloid (solid phase) and indium-Ill (liquid phase) w a s ingested at 0 min. The percent retention refers to the percentage of the radiolabelled marker remaining in the stomach over time (rain). Each point represents mean + SEM value for 32 studies in eight male subjects; four studies each. Reprinted from Brophy et al. (1986), with permission of the copyright holder, Plenum Publishing Corp., New York.

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healthy subjects. Gastric emptying was most rapid under fasting conditions. The delay in emptying of the markers was proportional to the frequency of feeding. Reprinted from Smith and Feldman (1986), with permission of the authors and the copyright holder, W. B. Saunders Co., Orlando.

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FIG. 3. Migrating motor complexes (MMCs) from 10 sites (duodenum to ileum) in a fasting healthy volunteer studied for 24 hr. Phase 3 waves correspond to MMCs. Note the aboral migration of most complexes. In the fasting state, MMCs occur at 90-120 min intervals. Reprinted from Fleckenstein and Oigaard (1978), with permission of the authors and the copyright holder, Plenum Publishing Corp., New York. beef stew and orange juice ingested were labeled with tracer doses of indium-I 11 (liquid phase) and 99m technetium-sulfur colloid (solid phase) allowing external scintillation monitors to observe the progress of gastric emptying. As observed in the figure, the time to 50% emptying for the liquid phase was approximately 25 min compared to 55 min for the solid phase. Thus, liquids typically empty more rapidly than digestible solids. Indigestible solids, represented by food particles greater than ~ 1 mm in diameter after trituration, and unable to pass through the pylorus, are emptied from the stomach by a third mechanism. Figure 2 illustrates the gastric emptying patterns of 2 mm and 10 mm inert markers, the latter comparing in size to enteric-coated tablets, during fasting and feeding (Smith and Feldman, 1986). Feeding markedly inhibited emptying of the inert markers and in proportion to the frequency of feeding. This effect is due to inhibition of the migrating motor complex (MMC), a particularly powerful 'housekeeping' wave that serves to sweep indigestible solids from the stomach into and through the small intestine. The MMC originates in the stomach and travels aborally at 90-120min intervals in man. These complexes are stimulated by fasting and the hormone motilin, and are promptly inhibited by feeding (Sarna, 1985). Figure 3 displays a 24 hr small intestinal motility pattern in a fasted, healthy subject (Fleckenstein and Oigaard, 1978). Note the peristaltic, aboral direction and regularity in timing of the MMC. Circadian rhythmic patterns superimposed on ultradian patterns is also characteristic of the healthy human GI tract. Figure 4 displays circadian rhythmicity in the speed of MMC propagation I0 A

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FIG. 4. Propagation velocity of human MMCs over 24 hr. Filled circles show 10 patients with irritable bowel syndrome; the open circles show 10 healthy subjects. The gap at 1800 hr shows the inhibiting influence of a meal on the MMC. In a companion meal-controlled porcine study, feeding did not alter the circadian pattern. Reprinted from Kumar et al. (1986), with permission of the authors and the copyright holder, W. B. Saunders Co., Orlando.

4

S . W . SANDERS and J. G. MOORE

along the small bowel in a group of healthy subjects and a group of patients with irritable bowel syndrome incubated with long pressure sensor-equipped intestinal tubes (Kumar et al., 1986). The daytime velocity of MMC propagation (cm/min) was more than double the nocturnal value in both groups. Gastric emptying rates for meals also display day and night differences (Goo et al., 1987). In a two time point study, displayed in Fig. 5, gastric emptying rates for meals administered at 2000 hr were significantly slower than emptying rates for the same meal administered to the same subjects at 0800 hr. In summary, liquids, digestible solids and indigestible solids empty from the stomach by different mechanisms and follow different time courses. These differences in gastric emptying have important implications for orally administered drugs and are influenced in major ways by ultradian and circadian rhythms in gastrointestinal motor function. 2.2. PHARMACOLOGY

Circadian alterations in gastric emptying rates, as described above, may result in delayed absorption of many oral medications administered during the evening. The delay is reflected by lower maximum plasma concentrations (Cmax) and longer times-to-peak drug plasma concentrations (Tmax). In Table 1, 9 of 10 drugs studied showed lower Cmax values when administered during the evening, compared to the morning. In all 4 studies where irmax values were available, longer Tma~values were observed following evening drug administration, compared to the morning. With few exceptions, however, the extent of absorption (bioavailability), reflected by the area under the plasma concentration-time curve (AUC), will remain unchanged (Clench et al., 1981; Markiewicz and Semenowicz, 1979a; Fig. 6). Valproic acid intestinal absorption, for example, is little affected over the circadian time frame (Fig. 7). Evening administration results only in a delayed Tmax time, with no significant change in Cmaxor AUC values between morning and evening (Yoshiyama et al., 1989). Circadian differences in absorption patterns between drugs may in part be explained by the rate of drug disintegration and dissolution within the gastric lumen. Drugs that completely dissolve are emptied as liquids and liquid phase emptying does not display the marked circadian variation observed with solids (Goo et al., 1987). Nevertheless, for some orally 6-

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FIG. 5. Gastric emptying rate for the solid portion of a meal eaten in the morning (AM) and evening (PM) FIG. 6. Mean plasma concentrations of indomethacin by 16 healthy male volunteers. Identical radiolabeled, in 9 healthy male volunteers following single 100 mg 300 g, 208 kcal beef stew meals were eaten at 0800 hr doses given at different times. TO was 0700, 1100, and 2000 hr on separate study days. Points represent 1500, 1900 and 2300 hr scheduled at weeklyintervals. mean (_ SEM) values. Asterisks represent significant Note the AM and PM differences in Cmax values; differences at p < 0.02 (*), <0.01 (**) and <0.001 AUC values, however, were not significantlydiffer(***) levels. Reprinted from Goo et al. (1987), with ent. Reprinted from Clench et al. (1981), with perpermission of the copyright holder, W. B. Saunders mission of the authors and the copyright holder, Springer-Verlag, Heidelberg. Co., Orlando.

Gastrointestinal chronopharmacoiogy TABLE 1. Summary of Reports on Circadian Differences in Oral Drug Absorption Compound

Parameters

Time of day (hr)

ASA 1500 mg

CmaX

0600 > 2 2 0 0

Indomethacin 100 mg Theophylline 4 mg/kg Theophylline

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Clorazepate dipotassium Erythromycin

Tmax (metabolite) C~ax

Ampicillin 500 mg D-zylose 10 gm FeSO4 100 mg Valproic acid 400 mg Omeprazole Diazepam 5 mg

AM > PM 1400 < 0200 0800 2000 0700 < 1900

Reference Markiewicz and Semenowicz, 1979a Clench et al., 1981 Clench et al., 1981 Kyle et al., 1980a Scott et al., 1981 Kyle et al., 1980b Lesko et al., 1980 Langner and Lemmer, 1988 Aymard and Soulaurac, 1979 DiSanto et al., 1975

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administered drugs, slower evening-time absorption may have therapeutic ramifications. For example, the time to Tmax for oral theophylline is delayed with evening, compared to morning administration, and this may be of benefit to asthmatic patients with increased nocturnal patterns of airway resistance (Reinberg et al., 1987). Slower evening-time absorption rates may also result in an increase in first-pass effect for high extraction compounds such as propanolal (Langner and Lemmer, 1988) and lead to lower bioavailability for omeprazole, a drug that is subject to gastric acid degradation (Prichard et al., 1985). Ingestion of medications with meals causes slower drug disintegration and dissolution and thus further delays absorption. The delay is exaggerated with drugs administered following evening meals because solid phase meal emptying is markedly slower in the evening compared to the morning hours (Goo et al., 1987; Fig. 5). Gastric emptying and absorption of enteric-coated or matrix-type sustained release drug products is even more delayed by concurrent meal ingestion. Food inhibits the intestine-originating MMC, as discussed above. These waves sweep indigestible solids, such as enteric-coated capsules, through the pylorus and into the small intestine where dissolution and absorption occurs. In the absence of MMCs, gastric residence time for these medications is prolonged (Bogentoft et al., 1978; Fig. 8). In addition, the propagation speed of MMCs also has a circadian rhythm with markedly slower rates in the nocturnal period (Kumar et aL, 1986; Fig. 4). Thus, enteric-coated drug formulations taken on an empty stomach during the evening hours, compared to morning administration, will be absorbed more slowly. There are no reports on circadian differences in effect of compounds acting directly on gastrointestinal smooth muscle. It might be anticipated, however, that prolonged gastric emptying would occur with evening time administration of anticholinergic and opiate medications. Conversely, the prokinetic action of metoclopramide or cisapride will be delayed with evening, compared to morning administration.

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THERAPEUTIC IMPLICATIONS

Circadian rhythmic changes in gastrointestinal motor function alter the pharmacokinetic profile of many drugs but the clinical impact of these alterations are minimal for most oral pharmaceuticals (Nakano and Hollester, 1978). There are a number of other metabolic factors, some of which display their own circadian rhythmic patterns, that confound and make the predictability of the effects of rhythmic changes in gastrointestinal motor function on drug disposition unreliable. These include circadian rhythmicity in hepatic microsomal activity (Belanger, 1988), and blood flow to the liver and kidneys that may affect the metabolism and/or elimination of drugs (Labrecque et al., 1988). In addition, circadian alterations in circulating plasma lipoprotein levels lead to changes in drug-protein binding capacity over the 24 hr period (Nakano et al., 1984). Nevertheless, most orally administered drugs will be absorbed more rapidly after morning administration with higher Cma, and shorter Tmaxvalues. This may be of clinical import for drugs with low toxicity thresholds, in which case evening administration may be more desirable. The evening hours are also the optimum delivery time for sustained-release theophylline preparations, as discussed above. Conversely, evening administration may be undesirable with some drugs because of a prolonged time to onset-of-action and, possibly, reduction in bioavailability and therapeutic effect. In some patients it may be useful to use alternative dosage forms. Liquid dosage forms will obviate the disintegration and dissolution steps necessary following oral solid (capsules or tablets) dosage forms and may speed absorption. Rectal or injectable routes of administration are other, less desirable, options that may be applicable to the individual patient.

3. GASTRIC ACID SECRETION 3.1. PHYSIOLOGY The human stomach is capable of secreting hydrochloric acid in concentrations that create a greater than 2 million fold gradient in hydrogen ion concentration between the gastric lumen and tissue vascular compartments. Acid secretion may be stimulated and blocked at histaminergic, cholinergic and gastrinergic sites on the surface of the parietal cell. In addition, the H ÷ -K ÷ ATPase receptor site at the cell apex may be blocked by proton pump inhibitors. The proton pump is

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FIG. 9. Twenty-four hr gastric acid (H +) chronogram from 14 healthy volunteers (circles) and 21 patients with active peptic ulcer (triangles). Points represent hourly mean (_ SEM) acid secretory rates. Note low morning and high evening secretion in both groups. Dashed line shows the mean 24 hr rate (5.76 + 0.98 mEq H +/hr) for the ulcer group; solid line shows mean rate (4.12 + 0.40 mEq H÷/hr) for the healthy group. Reprinted from Moore and Halberg (1986), with permission of the copyright holder, Plenum Publishing Corp., New York.

believed to be the final common pathway for hydrogen ion secretion into the gastric lumen. Pharmacological blockade of these receptor sites form the basis for modern day peptic ulcer treatment strategies. Under fasting conditions, acid is secreted in relatively low amounts to maintain an intragastric pH of approximately 1.5. This low-level rate is termed basal acid secretion. A circadian rhythm in basal gastric acid secretion has been reported in healthy men and in men with active duodenal ulcer disease (Moore and Halberg, 1986). The 24 hr acid secretory pattern for both groups shows that acid output is highest in the evening and lowest during the morning hours with higher mean rates of secretion (30% above controls) in the ulcer group (Fig. 9). The rate of basal acid secretion is highest between 9 pm and midnight. This pattern applies to individuals who maintain a diurnal active/nocturnal rest activity schedule. The mechanism(s) underlying gastric acid circadian rhythmicity is not fully understood although the vagus nerve appears to be an important factor. Rhythmicity in acid secretion is lost in post-vagotomy patients who continue to secrete significant amounts of basal gastric acid (Moore, 1973). The rhythmic changes in acidity are not accompanied by rhythmic changes in serum gastrin, an endogenous hormone known to stimulate acid secretion (Moore and Wolfe, 1973). Stimulation of parietal cell activity leads to significant increases in gastric acid secretion. Under physiological conditions, such as the ingestion of an ordinary meal, stimulated acid secretion quantitatively overwhelms basal rates by about 7-8 fold. Despite this dramatic increase in acid secretion, meals are generally associated with a transient elevation in intragastric pH due to the buffering effect of the meal. During interdigestive periods, intragastric pH gradually falls to basal or fasting levels again as a meal is emptied from the stomach. Thus, during the daytime hours, intragastric pH fluctuates, especially at mealtimes. During the nighttime hours, in the absence of food, intragastric pH remains low. It is believed that the nocturnal period is the time span during which the gastric mucosa is most vulnerable to damage and also most susceptible to acid inhibiting treatment strategies (Soll, 1989).

3.2. PHARMACOLOGY The pharmacologic treatment of peptic disease includes a wide array of medications aimed at inhibiting the effects of gastric acid. Treatments range from antacids for acid neutralization to

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FIG. 10. Sigmoidal EmaXdose-response relationship for famotidine and intragastric pH in a healthy subject (A) and ulcer patient (B). Solid circles show measured plasma concentrations, open circles indicate estimated plasma concentrations. ECs0% values for the two subjects were 26.0 ng/ml (A) and 32.6 ng/ml (B), respectively. Reprinted from Echizen et al. (1988), with permission of the authors and the copyright holder, The C. V. Mosby Co., St Louis. inhibition of acid secretion via the multiple pathways of acid stimulation discussed above. The H2-receptor antagonists are the most widely used antisecretory medications and are available in a variety of dosage forms for both oral and intravenous therapy. Simultaneous collection of plasma H2-receptor antagonist concentrations and gastric pH data reveal a sigmoidal dose-response relationship consistent with competitive inhibition of histamine action (Sanders et al., 1989; Echizen et al., 1988; Fig. 10). The clinical observation that patient's symptoms are exaggerated in the late evening and early morning hours has emphasized the need for evaluation of dosing regimens based on circadian rhythms (Freston, 1990). The circadian variation in basal acid secretion is apparent in studies using constant rate intravenous infusions of H2-receptor blockers. Intragastric pH decreases during the late evening (Sanders et al., 1988; Ballesteros et al., 1990; Fig. 11) matching the observed time of increased basal acid secretion. This rhythmic alteration in acid secretion results in a changing dose-response relationship for H2-receptor antagonists over the 24 hr period and it is apparent that higher doses of H2-blockers are required to inhibit basal acid secretion at times of peak acid secretion (Fig. 12) (Sanders et al., 1991, 1988; Merki et al., 1988). In addition, there is wide inter-patient variation in patient response to H2-receptor blockade that greatly affects dose requirements (White et al., 1991). Meals significantly increase acid secretion and reduce the effectiveness of antisecretory medications (Frislid and Berstad, 1985; Johnston and Wormsley, 1988; Ooi and Kaneko, 1989). A reduced antisecretory action has been shown for H2-receptor blockers alone and in combination with the anticholinergic agent, pirenzapine, following the evening meal (Ooi and Kaneko, 1989). 9° Placebo Control

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Gastrointestinal chronopharmacology

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FIG. 12. Pharmacodynamic relationship between acid secretion (H ÷) and serum ranitidine concentrations (Cp). Solid dark line indicates the relationship during the times of mean acid secretion (7.0 mmol/hr). Dashed lines show the relationship at acrophase and bathyphase, i.e. the times of maximum and minimum acid output (0.35 and 4.65 mmol/hr, respectively). Reprinted from Sanders et al. (1991), with permission of the copyright holder, Pergamon Press Ltd, Oxford. This effect of meals, in addition to the circadian influence, may result in loss of nighttime antisecretory activity (Merki et al., 1990a; Fig. 13). 3.3. THERAPEUTICIMPLICATIONS The observation of peak rates of acid secretion during the evening hours has provided a rationale for single bedtime doses of H2-blockers in the treatment of duodenal ulcer (Savarino et al., 1986). Increased evening basal gastric acid secretion coincides with and may augment meal-induced resistance to antisecretory treatment. Recent studies have indicated that H2-blockers should be administered after the final meal of the day to achieve optimum protection during the nocturnal time period (Merki et al., 1990b). Based on this evidence, dosage regimens which include multiple daily doses should incorporate a higher evening dose to achieve equal protection throughout the 24 hr period. 8 =

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10

S . W . SANDERS and J. G. MOORE

Other antisecretory agents have not been as extensively investigated for circadian differences in effect. Pirenzapine has been shown to inhibit nighttime acid secretion with a single evening dose (Howden et al., 1986). Evening dosing with omeprazole, compared to morning dosing, is associated with significantly reduced bioavailability, as discussed above, but further studies of circadian effects are needed (Pritchard et al., 1985). Future investigations of treatment regimens for peptic disease must consider the influence of circadian alteration in gastric function in their designs.

4. GASTRIC MUCOSAL DEFENSE 4.1. PHYSIOLOGY The major therapeutic aim in most peptic ulcer regimens is to reduce gastric acidity. It is also known, however, that more than half of all peptic ulcer patients exhibit normal, or less than normal, gastric acid secretory rates (Soll, 1989). In addition, a significant percentage of patients (10-20%) fail to respond to acid-suppressing medical or surgical treatments (Soll, 1989). It is for this reason that attention has been directed to alterations in mucosal defense factors in the pathogenesis of acid-peptic disorders. These factors include gastric epithelial cell mucous and bicarbonate secretion, prostaglandin production, gastric mucosal blood flow, cell wall bilayer phospholipid concentration, epithelial cell proliferation, migration and integrity, and gastric potential difference ( P D ) and electrical resistance (R) to ion movement, among others (Allan et al., 1984). 4.2. PHARMACOLOGY

In the experimental setting, several mucosal defense factors have been shown to display circadian rhythmicity. Ventura et al. (1987) reported circadian rhythms in gastric epithelial P D and R in exteriorized rat gastric mucosae (Fig. 14). The P D and R were maximal during the nocturnal or active period of this rodent species, following a similar rhythm in acid secretion in the same model. Larsen et al. (1991) demonstrated circadian rhythmicity in gastric acid secretion, bicarbonate secretion, tissue prostaglandin concentrations and mucosal blood flow in the intact rat model (Larsen et al., 1991a, b; Moore et al., 1991). In these latter studies, the acrophase (peak) of acid secretion was out of phase with the acrophase of bicarbonate secretion by 7 hr (Larsen et al., 1991 b; Fig. 15). Thus, a potential period of mucosal susceptibility to damage occurred when the normalized values of acid production exceeded bicarbonate production. Moreover, a circadian rhythm in damage to the mucosa produced by topically applied acetylsalicylic acid (ASA) was

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4 7 10 13 1(~ 19 22 ' HALO (Hours After Lights On) FIG. 15. Superimposed cosine curves showing the percentage fluctuation in acid and bicarbonate efflux in vivo in rats (p < 0.05). The acrophase (peak) for HCO3 secretion was different from H + secretion by 7 hr. Reprinted from Larsen et al. (1991b), The American Physiological Society, Bethesda. identified in the same model. Mucosal damage was correlated with the relative difference in acid to bicarbonate production (Larsen et al., 1991c). These findings suggest that mucosal damage by agents such as ASA is related to both increased acid secretion (an aggressive factor) and diminished bicarbonate secretion (a defensive factor). 4.3. THERAPEUTICIMPLICATIONS Similar investigations of factors of mucosal defense, requiring multiple samples over the' 24 hr time span, have not been reported in humans. A body of evidence in man, however, suggests that there are significant day-night differences in gastric mucosal damage induced by orally administered non-steroidal anti-inflammatory drugs (NSAIDs). One study reported that 5 of 10 patients experienced central nervous system or GI side effects after morning ingestion of indomethacin (100 mg) while only one of these patients had side effects if the same dose was taken in the evening (Huskisson, 1975). In a larger study, which included 517 osteoarthritic patients, orally administered sustained-release indomethacin produced significantly more undesirable side effects when administered at 0800 hr (30% of patients) compared to 2000 hr (9% of patients) (Levi et al., 1984). In a two time point study of 10 healthy male subjects, an orally administered 1300 mg dose of ASA produced 37% (p < 0.05) more damage to the gastric mucosa when given at 0800 hr than when given at 2000 hr (Moore and Goo, 1987; Fig. 16). Mucosal damage was assessed in this study by endoscopic counting of punctate, hemorrhagic lesions produced by ASA. These day-night differences in ASA-induced gastric mucosal damage were not correlated with differences in either gastric mucosal P D or in tissue concentrations of 6-keto-PgF2~, a metabolite of PG2 (Moore et al., 1988). These results were inconsistent with the observation that morning gastric acid secretory rates are lower than evening rates and the general acceptance that ASA-induced damage is acid ¢~

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0 22 10 22 Hour Hour FIG. 16. Median number of aspirin-induced gastric lesions followinga single 1300 mg morning and evening dose in 10 healthy volunteers. Evening administration produced 37% fewer lesions. Reprinted from Moore and Goo (1987), with permission of the copyright holder, Pergamon Press Ltd, Oxford. o

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S.W. SANDERSand J. G. MOORE

dependent. The dissociation of the circadian time of greatest acid secretion from that of maximal ASA-induced damage suggests that the presence of acid alone is not the sole determinant of ASA-induced tissue damage. Moreover, the greater morning-time ASA damage was not correlated with slower gastric emptying rates. Human gastric emptying rates are more rapid in the morning, when compared to the evening, which is consistent with the observation that morning-time absorption of ASA is also more rapid (Markiewicz and Semenowicz, 1979a). These findings together suggest that other, as yet unknown, factors of mucosal defense, and their possible circadian variation, are important additional determinants of drug-induced mucosal damage.

5. SEASONAL R H Y T H M S IN T H E I N C I D E N C E OF PEPTIC DISEASE Seasonal variation in the incidence of peptic ulcer disease has been explored in a number of large studies (Gibinski et al., 1982; Safrany et al., 1982; Bretzke, 1985; Palmas et al., 1984; Moshal et al., 1981; Heepe and Van Hausen, 1985; Karvonen, 1982; Ostensen et al., 1985). The variations which have been reported show a consistently lower incidence of peptic disease in the summer months and peak occurrences during the fall, winter or spring. In an endoscopically-based study, a significant increase in peptic recurrences was observed in the fall and spring (Gibinski, 1987). These observations, if confirmed in larger endoscopically-based studies, may lead to recommendations for seasonal preventative treatment schedules in this disease.

6. G A S T R O I N T E S T I N A L T O X I C O L O G Y Sections 4.2 and 4.3 discussed recent investigations on protective mechanisms of the gastric mucosa and their circadian variation. ASA-induced gastric mucosal toxicity, for example, was demonstrated to exhibit circadian rhythmicity. Gastrointestinal toxicity of cancer chemotherapeutic agents also displays circadian rhythmicity. The time of administration of these agents may be circadian staged to minimize toxic side-effects (Hrushesky, 1984). The basis for this salutary response may depend on the timing of the delivery of the agent to the proliferating intestinal 150Population Mean Cosinor Summary from least-squares fit of 24h cosine:* Y / /

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FIG. 17. Circadian waveform in incorporation of tritiated thymidine into rectal mucosal cell DNA (dpm/mcg DNA) in 16 men. Values expressed as a percentage of the mean value of incorporation over the entire 24-hour study period normalized to 100%. Reprinted from Buchi et al. (1991), with permission of the copyright holder, W. B. Saunders Company, Orlando.

Gastrointestinal chronopharmacology

13

epithelial cell. Circadian rhythms in cell proliferation have been reported for numerous tissues in animals, including the alimentary tract (Scheving et al., 1972, 1978). A circadian rhythm has also been reported for human rectal mucosal tissue (Buchi et al., 1991) (Fig. 17). Cellular D N A synthesis peaks in the early morning hr indicating that this may be the time when GI epithelial tissues are most susceptible to cellular injury induced by chemotherapeutic agents. A clinical trial upon cancer patients involving the continuous infusion of fluoropyrimidines versus a circadianbased administration schedule revealed reduced toxicity when the dose of medication was reduced between 0300 and 0900 hr (Roemeling and Hrushesky, 1987). Further studies of circadian-based dosing regimens will undoubtedly alter standard regimens for administration of toxic chemotherapeutic agents.

7. CONCLUSIONS Biological rhythms play an important role in both the pathogenesis and treatment of gastrointestinal diseases. Based on the patterns of known rhythms of physiological function, treatment schedules have been circadian adapted to provide optimum therapeutic benefit and/or minimize toxicity. The principles of chronotherapy are just now being recognized and their potential importance appreciated. Much work remains, however, and in future drug evaluations it will be important to design clinical trials and experimental procedures to take into account the influence of biological rhythms. Acknowledgements--Supported by DVA Medical Research, GI Section and University of Utah School of Medicine, Salt Lake City, Utah.

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Goo, R. H., MOORE,J. G., GREENBERG,E. and ALAZRAKI,N. P. (1987) Circadian variation in gastric emptying of meals in humans. Gastroenterology 93: 515-518. HEEPE, J. and VAN HAUSEN, N. (1985) Zur Hfiufigkeit und Lokalisation Gastroduodenalen Erosionen und Ulzere. Med. Welt. 36: 822-825. HOWDEN, C. W., BURGET, D. W., S1LETTI,C. and HUNT, R. H. (1986) Single nocturnal doses of pirenzapine effectively inhibit overnight gastric secretion. Hepatogastroenterology 32: 240-242. HRUSHESKY, W. J. M. (1984) Chemotherapy timing: An important variable in toxicity and response. In: Toxici O, of Chemotherapy, pp. 449-477, PERRY, M. C. and YARBRO, Y. W. (eds) Grune and Stratton, Philadelphia. HUSKISSON,E. C. (1976) Chronopharmacology of anti-rheumatic drugs with special reference to indomethacin. In: Inflammatory Arthropathies, pp. 99-105, HUSKISSON,E. C. and VELLO, G. P. (eds) Excerpta Medica, Amsterdam. JOHNSTON,D. A. and WORMSLEY,K. G. (1988) The effect of food on ranitidine-induced inhibition of nocturnal gastric secretion. Aliment. Pharmac. Ther. 2:507-511. KARVONEN,A. I. (1982) Occurrence of gastric mucosal erosions in association with other upper gastrointestinal diseases, especially peptic ulcer disease, as revealed by elective gastroscopy. Scand. J. Gastroenterol. 17: 977-984. KUMAR, D., WINGATE,D. and RUCKEBUSCH,Y. (1986) Circadian variation in the propagating velocity of the migrating motor complex. Gastroenterology 91:926 930. KYLE, G. M., SMOLENSKY,M. H., THORNE, L. G., HsI, B. P., ROBINSON,A. and McGoVERN, J. P. (1980a) Circadian rhythm in the pharmacokinetics of orally administered theophylline. In: Recent Advances in the Chronobiology of Allergy and Immunology, pp. 95-11 l, SMOLENSKY,M. H., REINBERG,A. and McGOVERN, J. P. (eds) Pergamon Press, Oxford. KYLE, G. M., SMOEENSKY,M. H., THORNE,L. G., HSl, B. P., ROBINSON,A. and McGOVERN,J. P. 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MOSHAL,M. G., SPITAELS,J. M., TOBBS,J. V., MACLEOD,I. N. and GOOD,C. J. (1981 ) Eight year experience with 3392 endoscopically proven ulcers in Durban 1972-1979. Gut 22: 327-331. NAKANO,S. and HOLLESTER,L. E. (1978) No circadian effect on nortriptyline kinetics in man. Clin. Pharmac. Ther. 23: 199-203. NAKANO,S., WATANABE,H., NAGAI,K. and OGAWA,N. (1984) Circadian stage-dependent changes in diazepam kinetics. Clin. Pharmac. Ther. 36: 271-277. Oot, S. and KANEKO,E. (1989) Gastric acid secretion stimulated by modified sham-feeding, and the effects of histamine H2-antagonist and anti-muscarinic agent in patients with duodenal ulcer. Gastroenterol. Japonica 24:505 511. OSTENSEN,H,, GUDMUNDSEN,T. E., BURHOL,P. G. and BONNEVILLE,O. (1985) Seasonal periodicity of peptide ulcer disease a prospective radiological study. Scand. J. Gastroenterol. 20: 1281-1284. PALMAS,F., ANDRIULLI,A., CANAPA,G., GERDINO,L., BOCRO,M., ROSSA,G. and VERME,G. (1984) Monthly fluctuations of active duodenal ulcers. Dig. Dis. Sci. 29: 983-987. PRICHARD,P, J., YEOMANS,N. D., MIHALY,G. W., JONES,D. G., BUCKLE,P, J., SMALLWOOD,R. A. and Louis, W. J. (1985) Omeprazole: A study of its inhibition of gastric pH and oral pharmacokinetics after morning and evening dosage. Gastroenterology 88: 64-69. REINBERG, A., PAUCHE, F., RUFF, F., GERVAIS,A., SMOLENSKY,M. H., LEVI, F., GERVAIS,P., CHAOUAT,O., ABELLA, L. and ZINDAI, R. (1987) Comparison of once daily evening versus morning sustained-release theophylline dosing for nocturnal asthma. Chronobiol. Int. 4(3): 409-420. ROEMELING,R. V. and HRUSHESKY,W. J. M. (1987) Circadian pattern of continuous FUDR infusion reduces toxicities. In: Advances in Chronobiology, Part B, pp. 357-373, PAULY,J. E. and SCHEVING,L. E. (eds) Liss, New York. SAFRANY,L., SCHOTT,B., PORTOCARRERO,G., KRAUSE,S. and NEWHAUS,n. (1982) Zur Frage der Fruhjahrs-und Herbstdisposition des Gastroduodenalen Ulzus. Deutsch Med Wschr 107: 685-689. SANDERS, S. W., MOORE, J. G., Bucm, K. N. and BISHOP,A. L. (1988) Circadian variation in the pharmacodynamic effect of intravenous ranitidine. A. Ret,. Chronopharrnac. 5: 335-338. SANDERS, S. W., BUCHI, K. N,, MOORE, J. G. and B1SHOP,A. L. (1989) Pharmacodynamics of intravenous ranitidine after bolus and continuous infusion in patients with healed duodenal ulcers. Clin. Pharmac. Ther. 46: 545-551. SANDERS, S. W., BALLESTEROS,M. A., HOGAN,D. K., KOSS, M. A. and ISENBERG,J. I. (1991) Effect of basal gastric acid secretion on the pharmacodynamics of ranitidine. Chronobiol. Int. 8: 186-193. SARNA, S. K, (1985) Cyclic motor activity migrating motor complex. Gastroenterology 89: 894-913. SAVARINO,V., MELA, G. S., SCALABRINI,P., DI TIMOTEO,E., MAGNOLIA,M. R., PERCARIO,G. and CELLE, G. (1986) Famotidine and ranitidine control of 24 h intragastric acidity after single bedtime administration; a study using continuous pH monitoring. Br. J. clin. Pharmac. 22: 749-750. SCriEVING,L. E., BURNS,E. R. and PAULY,J. E. (1972) Circadian rhythms in mitotic activity and 3H-thymidine uptake in the duodenum: effect of isoproterenol on the mitotic index. Am. J. Anat. 435:311-317. SCHEVING,L. E., BURNS,E. R., PAULY,J. E. and TSAI,T. H. (1978) Circadian variation and cell division of the mouse alimentary tract, bone marrow and corneal epithelium, Anat. Rec. 191: 479-486. SCOTT, P. H., TABACHNIK,E., MACLOED,S., CORREIA,J., NEWTH,C. and LEVlSON,H. (1981) Sustained-release theophylline for childhood asthma: evidence for circadian variation of theophylline pharmacokinetics. J. Pediat. 99: 476-479. SHARMA,D. S., DESHPANDE,V. A., SAMUEL,M. R. and VAKEL,I. J. (1979) Chronobioavailability of ampicillin. Chronobiologia 6:156. SMITH, H. J. and FELDMAN,M. (1986) Influence of food and marker length on gastric emptying of indigestible radiopaque markers in healthy humans. Gastroenterology 91: 1452-1455. SOLE, A. H. (1989) Duodenal ulcer and drug therapy. In: Gastrointestinal Disease Pathophysiology, Diagnosis, Management, 4th Edition, Ch. 47, pp. 814-879, SLEISENGER,M. H. and FORDTRAN,J. S. (eds) W. B. Saunders Co., Philadelphia. TARQUIN1, B., ROMANO, S., DE SCALZI, M., DE LEONARDIS,V., BENVENUTI,F., CHIGAI, E., COMPARINI,T. and CAGNONI,M. (1979) Circadian variation of iron absorption in healthy human subjects. In: Chronopharmacology, pp. 347-354, REINRERG,A. and HALBERG,F. (eds) Pergamon Press, Oxford and New York. VENTURA,U., CARANDENTEF., MONTINI,E. and CERIANI,T. (1987) Circadian rhythmicity of acid secretion and electrical function in intact and injured rat gastric mucosa--the relation of timing to ulcerogenesis. Chrono. Int. 4 (Suppl.): 43-52. WHITE,C., SMOLENSKY,M. H., SANDERS,S. W., BUCHI,K. N. and MOORE,J. G. (1991) Day-night and individual differences in response to constant-rate ranitidine infusion. Chronobiol. Int. 8: 56-66. YOSHIYAMA,Y., NAKANO,S. and OGAWA,N. (1989) Chronopharrnacokinetic study of valproic acid in man: Comparison of oral and rectal administration. J. Clin. Pharmac. 29: 1048-1052.