Comparative effects of carbamazepine and carbamazepine-10,11-epoxide on hepatic cytochromes P450 in the rat

Abstract

The effects of treatment with carbamazepine (CBZ), carbamazepine-10, 11-epoxide (CBZE), and phenobarbital (PB) on total hepatic cytochrome P450 and on cytochrome P450-mediated enzyme activity and protein levels were determined and compared in the present study. Adult male Long Evans 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 because serum levels of CBZE in patients on CBZ therapy are generally less than half those of the parent compound. The mean hepatic cytochrome P450 content for the CBZ treatment groups over the 14-day treatment period 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 total hepatic cytochrome P450. Pentoxyresorufin O-dealkylase and testosterone 2 beta-hydroxylase and 16 beta-hydroxylase activities, as well as androstenedione formation, were increased to a similar extent in CBZ-treated and PB-treated rats relative to the control groups. Immunoblot analysis indicated that hepatic levels of cytochromes P4502B1 and P4502B2 were highly induced, whereas cytochrome P4503A levels were increased slightly, by treatment with CBZ. In comparison, treatment with CBZE was approximately half as effective as CBZ for induction of pentoxyresorufin O-dealkylase activity, and for induction of cytochromes P4502B1/2B2 and cytochrome P4503A levels. In contrast, cytochrome P4501A1 and P4502E1 levels were not altered by treatment with CBZ, CBZE, or PB. The possibility that autoinduction of CBZ metabolism occurred was investigated, but urinary recoveries of CBZ, CBZE, and carbamazepine diol were too low to confirm this finding. In summary, the results demonstrated 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 used at this dosage, was as effective as PB for inducing hepatic cytochrome P450. Maximal induction by CBZE also occurred after 3 days of treatment, but the extent of induction was less than that produced by CBZ, possibly because of the smaller dose used.