Abstract
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.
Footnotes
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Send reprint requests to: Dr. Y. Kuroiwa, Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, 1–5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan.
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↵1 Present address: Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, 13–1 Takara-machi, Kanazawa 920, Japan.
- Abbreviations used are::
- CYP
- cytochrome P450
- NSAID
- nonsteroidal anti-inflammatory drug
- Received September 23, 1997.
- Accepted November 18, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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