title: Influence of co-medication on the metabolism of valproate.
abstract: 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.
authors.affiliation: First Neurological Clinic, University of Messina, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Pisani
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001711:Biotransformation; D004347:Drug Interactions; D006801:Humans; D008099:Liver / Q000187:drug effects; D010084:Oxidation-Reduction; D014635:Valproic Acid / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid; D001241:Aspirin