Valproic acid-carbamazepine interaction: is valproic acid a selective inhibitor of epoxide hydrolase?

Steady state plasma carbamazepine (CBZ), carbamazepine epoxide (CBZE), and carbamazepine diol (CBZD) concentrations were quantified by HPLC in 121 specimens obtained from two groups of epileptic patients: 78 receiving CBZ monotherapy (I), and 43 receiving CBZ and valproic acid (VPA) (II). The differences of drug/metabolite ratios and concentration/dose (mumol/L/mg/kg/day or 1/clearance) ratios were calculated as a measure for the influence of VPA on CBZ metabolism. Results as means +/- SD were CBZ/CBZE 5.85 +/- 3.91 (I) vs. 4.22 +/- 1.57 (II), p < 0.02; CBZ/CBZD 2.94 +/- 1.94 (I) vs. 2.82 +/- 1.15 (II); CBZE/CBZD 0.53 +/- 0.24 (I) vs. 0.71 +/- 0.32 (II), p < 0.001. Concentration/dose ratios: CBZ 2.32 +/- 1.58 (I) vs. 3.04 +/- 1.41 (II), p < 0.05; CBZE 0.41 +/- 0.20 (I) vs. 0.73 +/- 0.28 (II), p < 0.001; CBZD 0.82 +/- 0.35 (I) vs. 1.22 +/- 0.70 (II), p < 0.001. Drug/metabolite relationship data seem to support the concept for VPA as a selective inhibitor of epoxide hydrolase, but concentration/dose ratios indicate a reduced clearance for the parent drug, and especially for its two metabolites. This latter finding is in a controversy with the former concept. In addition, a considerable age-dependency of the influence of VPA on CBZ metabolism was found: compared to monotherapy, drug/metabolite and concentration/dose ratios were most changed in children. We assume that VPA is probably not a selective inhibitor of epoxide hydrolase, and affects nonspecifically all steps of the epoxide-diol pathway of CBZ metabolism.