Identification of cytochrome P450 isoform involved in the metabolism of YM992, a novel selective serotonin re-uptake inhibitor, in human liver microsomes

1. In vitro studies were conducted to identify the hepatic cytochrome P450 isoform involved in the metabolism of YM992, ((S)-2-[[(fluoro-4-indanyl)oxy ]methyl]morpholine monohydrochloride), a novel serotonin re-uptake inhibito r, in human liver microsomes. 2. Microsomes prepared from yeast expressing CYP1A1, CYP1A2 and CYP2D6 effe ctively metabolized YM992. A significant correlation was observed between t he rate of YM992 metabolism and 7-ethoxyresorufin O-deethylation, CYP1A1/2 specific activity, in liver microsomes from 16 individual donors (r(2) = 0. 628, p < 0.001). alpha-Naphtoflavone and isosafrole, CYP1A1/2 inhibitors, s uppressed the metabolism of YM992 in human liver microsomes in a concentrat ion-dependent manner. 3. The metabolism of YM992 in human liver microsomes was inhibited by simil ar to 95 % by antibodies which recognize both CYP1A1 and CYP1A2 whereas ant ibodies specific for CYP1A1 did net show inhibitory effects. 4. The same major metabolites, M6 and M7, were generated from YM992 after i ncubation with human liver microsomes and recombinant human CYP1A2. 5. These results suggest that the metabolism of YM992 in human liver micros omes is mainly catalysed by CYP1A2, and that YM992 might increase plasma co ncentration of concomitant drugs metabolized by CYP1A2 due to competitive i nhibition.