COMPARATIVE EFFECTS OF CARBAMAZEPINE AND CARBAMAZEPINE-10,11-EPOXIDE ON HEPATIC CYTOCHROMES-P450 IN THE RAT

The effects of treatment with carbamazepine (CBZ), carbamazepine-10,11 -epoxide (CBZE), and phenobarbital (PB) on total hepatic cytochrome P4 50 and on cytochrome P450-mediated enzyme activity and protein levels were determined and compared in the present study. Adult male Long Eva ns rats were treated intraperitoneally with either CBZ (100 mg/kg) or CBZE (50 mg/kg) every 12 hr for 3, 7, 10, or 14 days, or PB (75 mg/kg/ day) for 4 days. The dose of CBZE selected was half that of CBZ becaus e serum levels of CBZE in patients on CBZ therapy are generally less t han half those of the parent compound, The mean hepatic cytochrome P45 0 content for the CBZ treatment groups over the 14-day treatment perio d was 1,9-fold to 2.3-fold greater compared with the untreated group, whereas treatment with CBZE resulted in a more modest increase in tota l hepatic cytochrome P450. Pentoxyresorufin O-dealkylase and testoster one 2 beta-hydroxylase and 16 beta-hydroxylase activities, as well as androstenedione formation, were increased to a similar extent in CBZ-t reated and PB-treated rats relative to the control groups, Immunoblot analysis indicated that hepatic levels of cytochromes P4502B1 and P450 2B2 were highly induced, whereas cytochrome P4503A levels were increas ed slightly, by treatment with CBZ. In comparison, treatment with CBZE was approximately half as effective as CBZ for induction of pentoxyre sorufin O-dealkylase activity, and for induction of cytochromes P4502B 1/2B2 and cytochrome P4503A levels. In contrast, cytochrome P4501A1 an d P4502E1 levels were not altered by treatment with CBZ, CBZE, or PB. The possibility that autoinduction of CBZ metabolism occurred was inve stigated, but urinary recoveries of CBZ, CBZE, and carbamazepine diet were too low to confirm this finding. In summary, the results demonstr ated that cytochromes P4502B1 and P4502B2 are highly inducible by CBZ and CBZE. Maximal induction by CBZ occurred after 3 days of treatment at a dose of 100 mg/kg intraperitoneally every 12 hr and CBZ, when use d at this dosage, was as effective as PB for inducing hepatic cytochro me P450. Maximal induction by CBZE also occurred after 3 days of treat ment, but the extent of induction was less than that produced by CBZ, possibly because of the smaller dose used.