Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients.

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Gunes A, Bilir E, Zengil H, Babaoglu MO, Bozkurt A, Yasar U

Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients.

Basic Clin Pharmacol Toxicol. 2007 Jun;100(6):383-6. doi: 10.1111/j.1742-7843.2007.00061.x.

PubMed ID

17516991 [ View in PubMed

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Abstract

Drug interactions constitute a major problem in the treatment of epilepsy because drug combinations are so common. Valproic acid is a widely used anticonvulsant drug with a broad therapeutic spectrum. Case reports suggest interaction between valproic acid and other drugs metabolized mainly by cytochrome P450 isoforms. The aim of this study was to evaluate the inhibitory effect of valproic acid on cytochrome P450 2C9 (CYP2C9) activity by using losartan oxidation as a probe in epilepsy patients. Patients were prescribed sodium valproate (mean 200 mg/day for the first week and 400 mg/day in the following period) according to their clinical need. A single oral dose of 25 mg losartan was given to patients before and after the first dose, first week and 4 weeks of valproic acid treatment. Losartan and E3174, the CYP2C9-derived carboxylic acid metabolite of losartan in 8 hr urine were assayed by using high pressure liquid chromatography. Urinary losartan/E3174 ratio did not change significantly on the first day (0.9, 0.3-3.5; median, range), and first week (0.6, 0.2-3.8; median, range), while a significant increase was observed after 4 weeks of valproic acid treatment (1.1, 0.3-5.7; median, range) as compared to that of measured before valproic acid administration (0.6, 0.1-2.1; median, range) (P = 0.039). The degree of inhibition was correlated with the steady-state plasma concentrations of valproic acid (r(2) = 0.70, P = 0.04). The results suggest an inhibitory effect of valproic acid on CYP2C9 enzyme activity in epilepsy patients at steady state. The risk of pharmacokinetic drug-drug interactions should be taken into account during concomitant use of valproic acid and CYP2C9 substrates.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Valproic acid	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate Inhibitor	Details
Valproic acid	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate Inhibitor	Details