No significant effect of cimetidine on the pharmacokinetics of misonidazole in man.

Begg, EJ; Williams, Katie; Wade, DN; O'Shea, KF

doi:10.1111/j.1365-2125.1983.tb02096.x

Cited by 6 publications

(3 citation statements)

References 5 publications

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“…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. Steroid hydroxylation and epoxidation (carbamazepine) are also spared by cimetidine.…”

Section: The Cytochrome P-450 Mixed Functionmentioning

confidence: 61%

“…Thus any inhibition of cytochrome P-450 may enhance the tissue toxicity of misonidazole which mainly undergoes demethylation to form desmethylmisonidazole. Six subjects received misonidazole (1 gfm2) alone and following 1 week of pretreatment with cimetidine (1 gfday) [Begg et al 1983]. Cimetidine did not alter the AVC ofmisonidazole or its O-demethylated metabolite.…”

Section: Misonidazolementioning

confidence: 99%

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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: 61%

Section: Misonidazolementioning

confidence: 99%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

185

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“…In studies of other potential drug interactions, neither cimetidine nor metoclopramide altered the pharmacokinetics of misonidazole in healthy volunteers (Begg et al 1983;Williams et al 1983b) Due to its high lipophilicity and negligible protein binding, misonidazole demonstrates good penetration into various body tissues, including tumours, with tissue/plasma ratios ranging from 40 to 100%. However, the ratio was only 10% for body fat.…”

Section: Misonidazolementioning

confidence: 99%

Clinical Pharmacokinetics of Metronidazole and Other Nitroimidazole Anti-Infectives

Lau

Lam

Piscitelli

et al. 1992

Clinical Pharmacokinetics

184

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Metronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics. When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function. The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study.(ABSTRACT TRUNCATED AT 400 WORDS)

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The consequences of H2 receptor antagonist ? piroxicam coadministration in patients with joint disorders

Milligan

McGill

Howden

et al. 1993

Eur J Clin Pharmacol

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A randomised crossover study was performed in subjects with rheumatoid arthritis (or other arthropathies) to investigate if any alteration in the steady pharmacokinetics of the NSAID piroxicam (a drug which is extensively metabolised via cytochrome P450) or its major metabolites occurred as a result of coadministering either cimetidine or nizatidine. Twelve females and 2 males with mean age, weight, and albumin concentrations of 58 years, 61 kg, and 40 g.L-1 respectively, completed the study. Comparisons were made between the following parameters: plasma piroxicam AUCs [AUC0-24(P)], plasma 5-hydroxypiroxicam AUCs [AUC0-24(5-OHP)], the ratio of these i.e. AUC0-24(5-OHP):AUC0-24(p), the % piroxicam daily dose excreted in urine as 5-hydroxypiroxicam (before and after glucuronidase incubation); and the mean of the steady state trough piroxicam, and 5-hydroxypiroxicam concentrations (obtained during each study phase in addition to the wash-out period). A statistically significant difference as a result of initiating either cimetidine or nizatidine was obtained only for the ratio AUC0-23(5-OHP):AUC0-24(P). This was indicative of a weak potential to inhibit piroxicam hydroxylation. No clinically significant alteration in the steady state pharmacokinetics of piroxicam occurred in these subjects as a result of cimetidine or nizatidine coadministration. Consequently it is unlikely that any adverse events would arise from these combinations.

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No significant effect of cimetidine on the pharmacokinetics of misonidazole in man.

Cited by 6 publications

References 5 publications

Pharmacokinetic Interactions of Cimetidine 1987

Pharmacokinetic Interactions of Cimetidine 1987

Clinical Pharmacokinetics of Metronidazole and Other Nitroimidazole Anti-Infectives

The consequences of H2 receptor antagonist ? piroxicam coadministration in patients with joint disorders

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