RT Journal Article SR Electronic T1 Cytochrome P450 2C9 Catalyzes IndomethacinO-Demethylation in Human Liver Microsomes JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 261 OP 266 VO 26 IS 3 A1 Miki Nakajima A1 Tsuyoshi Inoue A1 Noriaki Shimada A1 Shogo Tokudome A1 Toshinori Yamamoto A1 Yukio Kuroiwa YR 1998 UL http://dmd.aspetjournals.org/content/26/3/261.abstract AB Indomethacin is a widely used nonsteroidal anti-inflammatory drug. We studied the human cytochrome P450 (CYP) isoform responsible for indomethacin O-demethylation, the major metabolic pathway for indomethacin. For indomethacin O-demethylase activities, the KM value was 34.6 ± 5.4 μM and the Vmax value was 14.1 ± 3.9 pmol/mg/min in human liver microsomes (N = 4). Indomethacin O-demethylase activity in human liver microsomes was competitively inhibited by sulfaphenazole, (S)-warfarin, and tolbutamide and was not affected by α-naphthoflavone, (S)-mephenytoin, or erythromycin. Indomethacin O-demethylase activities in microsomes from nine human livers were significantly correlated with tolbutamide hydroxylase activities (r = 0.750, p< 0.05) and not with (S)-mephenytoin 4′-hydroxylase activities. When the capacity for indomethacinO-demethylation in microsomes of B lymphoblastoid cells expressing human CYPs was investigated at an indomethacin concentration of 5 μM, cDNA-expressed CYP2C9 exhibited 6-fold greater activity than did CYP2C19. At an indomethacin concentration of 50 μM, cDNA-expressed CYP1A2 and CYP2D6 also exhibited slight activities. TheKM values were 9.9 ± 1.2 and 117.1 ± 13.8 μM and the Vmaxvalues were 0.33 ± 0.05 and 0.24 ± 0.04 pmol/min/pmol CYP in microsomes with cDNA-expressed CYP2C9 and CYP2C19, respectively (N = 4). Considering the 16-fold higher intrinsic clearance of CYP2C9, compared with that of CYP2C19, and these expression levels in human livers, the contribution of CYP2C19 to indomethacin O-demethylation was considered to be negligible. Indomethacin appears to be O-demethylated exclusively by CYP2C9 in humans. The American Society for Pharmacology and Experimental Therapeutics