IN-VIVO CIMETIDINE INHIBITS HEPATIC CYP2C6 AND CYP2C11 BUT NOT CYP1A1IN ADULT MALE RATS

We previously reported that in vivo cimetidine inhibits hepatic micros omal enzyme activities mediated by cytochrome P450 (CYP)2C11 and at le ast one other CYP enzyme but does not inhibit CYP2A1-, CYP2B- or CYP3A -mediated activities in adult male rats. To investigate the effects of in vivo cimetidine on CYP1A1, cimetidine (150 mg/kg i.p.) or saline w as administered to beta-naphthoflavone-induced (40 mg/kg i.p. once dai ly for 3 consecutive days) or uninduced adult male Wistar rats, and he patic microsomes were prepared 90 min after the cimetidine injection, Cimetidine had no effect on either methoxyresorufin O-dealkylase (MROD ) or ethoxyresorufin O-dealkylase (EROD) activity in microsomes from b eta-naphthoflavone-induced rats. In these same microsomes, polyclonal anti-CYP1A1 IgG inhibited both MROD and EROD activities by >90%, where as monoclonal anti-CYP1A1 IgG inhibited MROD and EROD activities by 60 % and 80%, respectively. In contrast, cimetidine inhibited MROD and ER OD activities in microsomes from uninduced rats by 50% and 65%, respec tively (P <.05). Immunoinhibition studies with polyspecific and monosp ecific anti-CYP2C11 IgG indicated that MROD and EROD activities are me diated by a CYP2C enzyme or enzymes other than CYP2C11 in these micros omes. To investigate the possibility that the drug affected EROD activ ity in uninduced rats by inhibiting CYP2C6, cimetidine was administere d as described to rats that had been pretreated with phenobarbital (80 mg/kg i.p once daily for 4 consecutive days). In hepatic microsomes f rom these rats, cimetidine inhibited progesterone 21-hydroxylase activ ity (mediated by CYP2C6) by 62% and progesterone 2 alpha-hydroxylase a ctivity (mediated by CYP2C11) by 39% but had no effect on progesterone 6 beta-hydroxylase activity (mediated by CYP3A). Taken together, the results indicate that in vivo cimetidine has no effect on CYP1A1 but i nhibits CYP2C6 in addition to CYP2C11. Preincubation of microsomes fro m uninduced rats with cimetidine and NADPH in vitro increased the pote ncy of inhibition of EROD activity by 20-fold, suggesting that cimetid ine inhibits CYP2C6, as it does CYP2C11: by forming a metabolite/inter mediate complex.