Lack of inhibition of tolbutamide hydroxylation by cimetidine in man

Stockley, Creina S.; Keal, Julie; Rolan, Paul; Bochner, Felix; Somogyi, Andrew A.

doi:10.1007/bf00606666

Cited by 14 publications

(7 citation statements)

References 8 publications

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“…Grygiel et al (1984) reported that while cimetidine inhibited 3-and 7-demethylation of theophylline, there was no inhibition of 8-oxidation. Dey et al (1983) found a lack of effect of cimetidine on tolbutamide plasma concentrations, which was confirmed by Stockley et al (1986), who found no change in tolbutamide hydroxylation clearance in humans. Conrad et al (1984) showed a lack of inhibition of ibuprofen clearance by cimetidine, observed a similar phenomenon with mexiletine, and Begg et al (1983) with misonidazole.…”

Section: The Cytochrome P-450 Mixed Functionmentioning

confidence: 64%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

185

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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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Section: The Cytochrome P-450 Mixed Functionmentioning

confidence: 64%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

185

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“…Lignocaine undergoes substantial amide hydrolysis (Mihaly et al, 1978) whereas the major routes of the metabolism of bupivacaine in man are poorly documented (Tucker & Mather, 1979). The fact that cimetidine is a selective inhibitor of drug metabolism is exemplified by the finding that cimetidine impairs the 3-and 7-demethylation but not the 8-hydroxylation of theophylline (Crygiel et al, 1984), and that it is without influence on the hydroxylation of tolbutamide (Stockley et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Lack of effect of cimetidine on the pharmacokinetics of bupivacaine in healthy subjects.

Pihlajamäki

Lindberg

Jantunen

1988

Brit J Clinical Pharma

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1 The possibility of a pharmacokinetic interaction between the H2-receptor antagonist cimetidine and the long-acting local anaesthetic agent bupivacaine was studied in seven healthy, non-smoking volunteers. 2 The study consisted of two sessions at a minimum interval of 4 days. In a randomized, crossover fashion, the volunteers received bupivacaine HC1 1.4 mg kg-' by i.m. injection at two occasions, once after no premedication, and once after two oral doses of 400 mg cimetidine. The concentrations of bupivacaine and its metabolites, 4'-hydroxybupivacaine and desbutylbupivacaine, were assayed by h.p.l.c., in serum up to 8 h and in urine fractions up to 24 h. 3 No influence of cimetidine on the pharmacokinetics of bupivacaine or on the serum cumulation of urinary recovery of its measured metabolites was detected. 4 These data suggest that cimetidine may be used safely as a premedication before local anaesthetic procedures with bupivacaine.

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“…When cimetidine was administered at dosages of 1200 and 1600 mgjday, tolbutamide half-life and AUC increased and clearance decreased (Back et al 1988;Cate et al 1986). However, at lower doses of 800 and 1000 mgjday, cimetidine had no significant effect on tolbutamide pharmacokinetics (Back et al 1988;Dey et al 1983;Stockley et al 1986). In contrast, Adebayo & Coker (1988) reported that cimetidine 1200 mgjday had no effect on tolbutamide disposition.…”

Section: Other Agentsmentioning

confidence: 92%

“…Monitor drug Choonara et al (1986); Hetzel et al levels, adjust (1979) Toon et al (1986Toon et al ( , 1987; Wallin et al (1979) No Pachon et al (1989); Puff et al (1989); Zylber-Katz (1988) No Fraley et al (1983); Garty et al (1986); Jordaens et al (1981); Ochs et al (1984) No Harvey et al (1984) No Gugler et al (1983) No Back et al (1988); Cate et al (1986); Dey et al (1983); Stockley et al (1986) Abbreviations: C = serum/blood/plasma drug concentration; AUC = area under the concentration-time curve; t'l2 = elimination halflife; CL = clearance.…”

Section: Theophyllinementioning

confidence: 97%

Clinical Relevance of Cimetidine Drug Interactions

Shinn

1992

Drug Safety

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The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

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Lack of inhibition of tolbutamide hydroxylation by cimetidine in man

Cited by 14 publications

References 8 publications

Pharmacokinetic Interactions of Cimetidine 1987

Pharmacokinetic Interactions of Cimetidine 1987

Lack of effect of cimetidine on the pharmacokinetics of bupivacaine in healthy subjects.

Clinical Relevance of Cimetidine Drug Interactions

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