TY - JOUR T1 - Multiple Cytochrome P450 Enzymes Responsible for the Oxidative Metabolism of the Substituted (<em>S</em>)-3-Phenylpiperidine, (<em>S</em>,<em>S</em>)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine Hydrochloride, in Human Liver Microsomes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1372 LP - 1377 DO - 10.1124/dmd.30.12.1372 VL - 30 IS - 12 AU - Larry C. Wienkers AU - Michael A. Wynalda Y1 - 2002/12/01 UR - http://dmd.aspetjournals.org/content/30/12/1372.abstract N2 - (S,S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride [(−)-OSU6162] is a weak dopamine D2 receptor modulator that possesses potential for the treatment of levodopa (l-DOPA)-induced dyskinesias in patients with Parkinson's disease. In this report, incubations with human liver microsomes revealed that (−)-OSU6162 is selectively metabolized viaN-dealkylation to yield N-depropyl (−)-OSU6162. Kinetics evidence is presented that theN-depropylation of (−)-OSU6162 in human hepatic microsomes is mediated by multiple cytochrome P450 (P450) enzymes, in particular CYP2D6. This hypothesis is borne out by several lines of in vitro evidence; 1) incubations of (−)-OSU6162 (5 μM) with hepatic microsomes from a panel of human donors showed that (−)-OSU6162N-depropylase activity correlated well with CYP2D6-catalyzed dextromethorphan O-demethylase activity but not with other P450 enzyme-specific activities; 2) quinidine, a CYP2D6-specific inhibitor, inhibited (−)-OSU6162N-depropylation, whereas other P450 enzyme-specific substrates/inhibitors did not significantly inhibit this activity; 3) CYP2D6 possessed highest intrinsic (−)-OSU6162N-depropylase activity when compared with a battery of recombinant heterologously expressed human P450 enzymes. In addition, the selectivity of (−)-OSU6162 to inhibit six human P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2E1, CYP2D6 and CYP3A4) was evaluated using an in vitro inhibition screen. Of the enzymes examined, only the activity of CYP2D6 was inhibited by coincubation with (−)-OSU6162. Thus, it is concluded that (−)-OSU6162 is metabolized by several P450 enzymes and that CYP2D6 accounts for the majority of the observed P450N-depropylase activity in vitro. The American Society for Pharmacology and Experimental Therapeutics ER -