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

Drug interactions constitute a major problem in the treatment of epilepsy because drug combinations are common. Case reports suggest an interaction between valproic acid and drug substrates of CYP2C9. The aim of this study was to evaluate the inhibitory effect of valproic acid on CYP2C9 activity by using losartan oxidation as a marker in epilepsy patients. A single oral dose of 25 mg losartan was given to patients (n=11) at the baseline. Losartan and its CYP2C9 derived metabolite E3174 were assayed in 8‐hour urine samples by using HPLC. The same procedure was repeated after the first dose and at the completion of the first and fourth weeks of valproic acid treatment. Urinary losartan/E3174 ratio (median, range) did not change significantly at the first day or the first week, while a significant increase was observed at the fourth week of valproic acid treatment (1.09, 0.28–5.71) as compared with the baseline (0.60, 0.10–2.07) (P=0.039). The degree of inhibition was correlated with the steady state plasma concentrations of valproic acid (r 2 =0.82, P=0.018). These results provide an in vivo evidence that valproic acid is an inhibitor of CYP2C9 at concentrations reached during steady state in human. The risk of pharmacokinetic drug‐drug interactions should be considered during concomitant use of valproic acid and CYP2C9 substrates. (Supported by TUBITAK‐SBAG COST B25‐105S027 and UY/TUBA‐GEBIP/2005‐17)