カルバマゼピン活性代謝物のカルバマゼピンエポキシドの血中濃度は低年齢でバルプロ酸の血中濃度が高いほど上昇する

Abstract

Carbamazepine (CBZ), a first-line drug in the treatment of epilepsy, is mainly metabolized in the liver to carbamazepine-10, 11-epoxide (CBZ-epoxide), an active metabolite of carbamazepine. Which is subsequently converted by epoxide hydrolase to trans-10. 11-dihydroxy-10, 11-dihydro-carbamazepine (CBZ-diol). It is well known that the combination of CBZ and valproic acid (VPA), which have an inhibitory effect on epoxide hydrolase, results in an increased serum CBZ-epoxide concentration, and that such drug interaction produces clinically relevant side effects. In the present study, the steady state serum concentrations of CBZ, CBZ-epoxide and CBZ-diol were measured by HPLC in 46 epileptic patients (from 7 months to 19 years of age) who were receiving CBZ monotherapy or 36 epileptic patients (from 1 year to 19 years of age) who were receiving CBZ and valproic acid, in order to investigate the influences of age and the VPA combination on the CBZ metabolism. The concentration ratio of CBZ-epoxide / CBZ in patients receiving CBZ monotherapy decreased with increasing age, but the ratio of CBZ-diol / CBZ-epoxide did not show any significant age dependency. These results suggest that the ability of the biotransformation from CBZ to CBZ-epoxide is higher in younger aged patients. On the other hand, the combination with CBZ and VPA produced a marked increase in the CBZ-epoxide / CBZ ratio and a marked decrease in CBZ-diol / CBZ-epoxide ratio in a VPA serum concentration-dependent manner, thus indicting an inhibitory effect of VPA on epoxide hydrolase. These findings provide evidence that the serum concentration of CBZ-epoxide, an active metabolite of carbamazepine, is higher in younger aged patients and in those with a higher serum concentration of VPA.