Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics

Webster, Lorraine K.; Mihaly, G W; Jones, D. E.; Smallwood, R A; Phillips, J. A.; Vajda, Frank J. E.

doi:10.1007/bf00542172

Cited by 36 publications

(11 citation statements)

References 15 publications

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“…The pharmacokinetics of carbamazepine differ markedly between single and long term dosing due to the occurrence of autoinduction of metabolism. Webster et al (1984) found a small effect oflong term cimetidine (1 g/day for 6 weeks) on the pharmacokinetics of a single dose of carbamazepine 400mg. Cimetidine significantly reduced the clearance from a mean of 20.3 to 18.0 mlfmin (1.22 to 1.08 L/h) with no effect on the half-life, in peptic ulcer patients.…”

Section: Carbamazepinementioning

confidence: 97%

“…The metabolism of sodium valproate is inducible by agents such as phenobarbitone and phenytoin, reflecting involvement of the cytochrome P-450 mixed function oxidase system. Webster et al (1984) reported a small effect of cimetidine on the disposition of sodium valproate in peptic ulcer patients receiving 1 gfday of cimetidine. In 5 of the 6 patients oral clearance of sodium valproate decreased by between 2 and 17%, which is not statistically significant.…”

Section: Sodium Valproatementioning

confidence: 97%

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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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Section: Carbamazepinementioning

confidence: 97%

Section: Sodium Valproatementioning

confidence: 97%

Pharmacokinetic Interactions of Cimetidine 1987

Somogyi

Muirhead

1987

Clinical Pharmacokinetics

184

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“…Ranitidine treatment did not change the pharmacokinetic profile of carbamazepine (Dalton et al 1985;Webster et al 1984), valproic acid (Webster et al 1984) or phenytoin (Watts et al 1983) in studies conducted either in healthy volunteers or in patients with epilepsy or duodenal ulcers. Although no clinical reports of drug interactions have been reported involving the first 2 compounds, a recent paper mentioned a possible interaction between ranitidine and phenytoin in a 66-year-old patient who developed a symptomless 40% increase in plasma phenytoin concentrations after several days of ranitidi~e treatment (Bramhall & Levine 1988).…”

Section: Antiepilepticsmentioning

confidence: 96%

Side Effects of Ranitidine

et al. 1991

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Ranitidine was first marketed in 1981; since then many patients have been treated such that much experience has been accumulated on the safety of this histamine H2-receptor antagonist in the treatment of gastroduodenal disease. A wide array of ranitidine-associated side effects has been described, but infrequently. As so much information is now available, the aim of this review is to assess the weight of evidence for a causal link between ranitidine and the reported side effects. Overall, ranitidine is well tolerated. The incidence of general side effects at less than 2% is very similar to placebo. Headaches, tiredness, dizziness and mild gastrointestinal disturbance (e.g. diarrhoea, constipation and nausea) are among the most frequent complaints, but have very seldom resulted in stopping treatment. Cardiovascular side effects are extremely rare and unpredictable with the usual doses of oral ranitidine (at most 1 in 1 million patients). They mostly comprise sinusal bradycardia and atrioventricular blockade, especially after rapid intravenous administration, receding after cessation of the drug. Clinical studies, however, have not shown a significant pharmacological effect of ranitidine on the cardiovascular system via H2-receptors, even though individual sensitivities cannot be ruled out in a few isolated reports. Ranitidine is unlikely to be directly hepatotoxic: a transient change in liver function tests has been noted in only 1 in 100 to 1 in 1000 patients. Several cases of mixed hepatitis have been reported, but very few were fully documented. The incidence of ranitidine-associated acute hepatitis has been estimated to be less than 1 in 100,000 patients. Neuropsychiatric complications may be less common and clinically quite similar to those reported with cimetidine, i.e. confusion, disorientation, hallucinations, delirium. These side effects have occurred especially in critically ill and multiple-therapy patients, or patients with chronic renal or hepatic failure, so that the direct causal link with ranitidine treatment was often difficult to ascertain. Even though an H2-receptor-mediated effect is an attractive hypothesis (since similar complications were noted with other H2-receptor antagonists), other mechanisms have been suggested to play a role, e.g. cholinergic or histaminic effects. The overall incidence of neuropsychiatric complications is probably markedly less than 1%. White cell injury (i.e. agranulocytosis) appears to be the most frequent haematological complication, even though case reports are very few and poorly documented.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…A 2 to 17% fall in VPA total clearance accompanied by a statistically significant prolongation of elimination serum half-life (from 9.6_+1.6 to 11.0_+2.0h, mean values • p<0.02) has been reported to occur in 5 of the 6 cimetidinetreated patients [31].…”

Section: Fundamentals Of Valproate Metabolism In Humansmentioning

confidence: 97%

Influence of co-medication on the metabolism of valproate

Pisani

1992

Pharmaceutisch Weekblad Scientific Edition

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Valproate is extensively metabolized in the liver and at least six main pathways which produce about 50 metabolites have been identified in man. The enzyme-inducing antiepileptic drugs phenobarbital, primidone, phenytoin and carbamazepine increase total valproate clearance by 30-85%, whereas cimetidine and the new anticonvulsant compound striripentol display a small inhibitory effect (10-20%). Both carbamazepine and phenytoin induce a two-fold increase in the formation of delta 4-valproate and stimulate omega-oxidation and omega-1-oxidation. Acetylsalicylic acid causes a fall of 60-70% in the content in the urine of the metabolites of the beta-oxidative pathway, i.e. delta 2-valproate, 3-OH-valproate and 3-oxo-valproate, and an increase of glucuronidation (approximately 30%) and delta-dehydrogenation (approximately 20%). Stiripentol inhibits the formation clearance of delta 4-valproate by 30%. In the light of the possible therapeutic and toxic effects of some valproate metabolites, drug interactions with valproate at metabolic level may have important clinical implications.

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Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics

Cited by 36 publications

References 15 publications

Pharmacokinetic Interactions of Cimetidine 1987

Pharmacokinetic Interactions of Cimetidine 1987

Side Effects of Ranitidine

Influence of co-medication on the metabolism of valproate

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