Decreased systemic clearance of caffeine due to cimetidine.

Broughton, L. J.; Rogers, H. J.

doi:10.1111/j.1365-2125.1981.tb01194.x

Cited by 47 publications

(9 citation statements)

References 23 publications

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“…Cigarette smoking has been reported to increase caffeine clearance due to induction of hepatic aryl hydrocarbon hydroxylase activity (14)(15)(16). On the other hand, cimetidine and disulfiram have been shown to inhibit that clearance (15,17,18). In the present study, there was no difference in fasting plasma caffeine concentration between smokers and nonsmokers, and cimetidine and disulfiram were not administered to the patients.…”

Section: Resultscontrasting

confidence: 75%

Fasting Plasma Caffeine Level in Cirrhotic Patients: Relation to Plasma Levels of Catecholamines and Renin Activity

1989

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Fasting plasma caffeine concentrations, plasma levels of catecholamines and plasma renin activity were measured in patients with cirrhosis and control patients without hepatic dysfunction. A careful dietary history showed no significant difference in caffeine consumption (mean +/- S.E.) among 46 cirrhotics (86 +/- 7 mg per day) vs. 34 control patients (91 +/- 8 mg per day). Fasting plasma caffeine concentrations, however, were significantly higher (7.68 +/- 1.42 micrograms per ml) in cirrhotics than in controls (1.01 +/- 0.20 micrograms per ml) (p less than 0.01). Fasting plasma caffeine concentrations in cirrhotics varied significantly with Child's criteria, namely Child's A patients (2.06 +/- 0.38 micrograms per ml); Child's B patients (6.92 +/- 1.86 micrograms per ml), and Child's C patients (17.70 +/- 3.65 micrograms per ml) (p less than 0.001). In 44 cirrhotics, fasting plasma caffeine concentrations were compared with plasma levels of catecholamines and plasma renin activity. Plasma epinephrine concentrations were normal; however, plasma norepinephrine concentrations were increased in six cirrhotics, and plasma renin activities were increased in 28 cirrhotics. After a 3-day caffeine abstinence, plasma caffeine concentration and renin activity were significantly decreased (p less than 0.01), and high plasma norepinephrine levels were also decreased in 12 cirrhotics. Plasma caffeine concentration, renin activity and norepinephrine level did not change in a control group of cirrhotics who continued to receive caffeine for 3 days (n = 6). After abstinence from caffeine, the decrease of fasting plasma caffeine concentration correlated well with the decrease of plasma renin activity (r = +0.746, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Resultscontrasting

confidence: 75%

Fasting Plasma Caffeine Level in Cirrhotic Patients: Relation to Plasma Levels of Catecholamines and Renin Activity

1989

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“…Both excretion fractions and the more critical partial clearance equivalents corresponded very well to previous, more formal pharmacokinetic studies [27,34,40], even though the scatter of the present data is wider probably due to the influence of the many uncontrolled variables. Both excretion fractions and the more critical partial clearance equivalents corresponded very well to previous, more formal pharmacokinetic studies [27,34,40], even though the scatter of the present data is wider probably due to the influence of the many uncontrolled variables.…”

Section: Discussionsupporting

confidence: 87%

Urinary caffeine metabolites in man

Ullrich

Compagnone

Münch

et al. 1992

Eur J Clin Pharmacol

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In an exploratory study the 24-h urinary excretion pattern of caffeine and 14 of its major metabolites was studied in 32 volunteers (adults, adolescents and children), 14 patients either with end stage renal disease or liver cirrhosis, 7 heavy smokers and 27 patients on therapy with cimetidine, allopurinol, theophylline or phenytoin. Caffeine and its metabolites were quantified by UV-absorption after liquid/liquid-extraction and HPLC-separation, which ensured proper analysis of 1-methyluric acid. In adults the renal excretion of caffeine derivatives corresponded to an intake of 509 mg caffeine/day, with 1-methyluric acid as the predominant metabolite. About 69% of caffeine was degraded by the paraxanthine pathway, and theobromine- (19%) and the theophylline pathway (14%) were less important. The ratio of paraxanthine formation to urinary caffeine concentration (= clearance equivalent) was about 2.2 ml.min-1.kg-1 in adults, and the corresponding ratios for theophylline and theobromine were 0.43 ml.min-1.kg-1 and 0.59 ml.min-1.kg-1, respectively. As expected, caffeine degradation was impaired in patients with cirrhosis and was increased in persons who smoked heavily or who were on phenytoin therapy. The results document the possibility of noninvasively investigating gross differences in caffeine disposition by analysis of the urinary pattern of its metabolites.

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“…Since caffeine is metabolised by similar metabolic pathways to theophylline, alterations in its metabolism by cimetidine might be anticipated. In the first reported study, Broughton and Rogers (1981) investigated 5 nonsmokers who took a single oral dose of caffeine 300mg with and without cimetidine 1 g/day in divided doses. Caffeine clearance declined in 4 of the subjects by between 36 and 49%, and in the other subject by 2%.…”

Section: Caffeine (137-trimethylxanthine)mentioning

confidence: 99%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

184

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The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active.(ABSTRACT TRUNCATED AT 400 WORDS)

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Decreased systemic clearance of caffeine due to cimetidine.

Cited by 47 publications

References 23 publications

Fasting Plasma Caffeine Level in Cirrhotic Patients: Relation to Plasma Levels of Catecholamines and Renin Activity

Fasting Plasma Caffeine Level in Cirrhotic Patients: Relation to Plasma Levels of Catecholamines and Renin Activity

Urinary caffeine metabolites in man

Pharmacokinetic Interactions of Cimetidine 1987

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