Da. Svinarov et Ce. Pippenger, VALPROIC ACID-CARBAMAZEPINE INTERACTION - IS VALPROIC ACID A SELECTIVE INHIBITOR OF EPOXIDE HYDROLASE, Therapeutic drug monitoring, 17(3), 1995, pp. 217-220
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 re
ceiving CBZ monotherapy (I), and 43 receiving CBZ and valproic acid (V
PA) (II). The differences of drug/metabolite ratios and concentration/
dose (mu mol L/mg/kg/day or 1/clearance) ratios were calculated as a m
easure 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) v
s. 1.22 +/- 0.70 (II), p < 0.001. Drug/metabolite relationship data se
em 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 latt
er 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 prob
ably not a selective inhibitor of epoxide hydrolase, and affects nonsp
ecifically all steps of the epoxide-diol pathway of CBZ metabolism.