Celecoxib is a substrate of CYP2D6: Impact on celecoxib metabolism in individuals with CYP2C9*3 variants |
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| Institution: | 1. Drug Metabolism and Pharmacokinetics Department, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA;2. Chemical Biology Department, Eisai Inc., 4 Corporate Drive, Andover, MA, USA;1. Dokuz Eylül University School of Medicine, Department of Otorhinolaryngology, Izmir, Turkey;2. Dokuz Eylül University Institute of Oncology, Department of Basic Oncology, Izmir, Turkey;3. Dokuz Eylul University School of Medicine Department of Otorhinolaryngology, Unit of Hearing Speech and Balance, Izmir, Turkey;4. Dokuz Eylül University School of Medicine, Department of Pediatric Oncology, Izmir, Turkey;5. Dr Behçet Uz Children''s Hospital, Department of Pediatric Oncology, Izmir, Turkey;6. Dokuz Eylül University School of Medicine, Department of Biostatistics, Izmir, Turkey;1. Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan;2. Department of Urology, Tokyo Women''s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan;3. Laboratory for Safety Assessment and ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokunishi, Shizuoka 410-2321, Japan;4. Medical Affairs Department, Pharmaceutical Business Administration Division, Asahi Kasei Pharma Corporation, 1-105 Kanda Jimbocho, Chiyoda-ku, Tokyo 101-8101, Japan;5. Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan;6. Department of Nephrology, Tokyo Women''s Medical University, Yocho-machi Clinic, Yocho-machi 6-21, Shinjuku, Tokyo 162-0055, Japan;1. College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea;2. Department of Medical Management, Chodang University, 380 Muan-ro, Muan-eup, Muan-gun, Jeollanam-do 58530, South Korea;1. Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan;2. Showa Pharmaceutical University, Machida, Japan |
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| Abstract: | Celecoxib was characterized as a substrate of human cytochrome P450 (CYP) 2D6 in vitro. In recombinant CYP2D6, celecoxib hydroxylation showed atypical substrate inhibition kinetics with apparent Km, Ki, and Vmax of 67.2 μM, 12.6 μM, and 1.33 μM/min, respectively. In human liver microsomes (HLMs), a concentration-dependent inhibition of celecoxib hydroxylation by quinidine was observed after CYP2C9 and CYP3A4 were inhibited. In individual HLMs with variable CYP2D6 activities, a significant correlation was observed between celecoxib hydroxylation and CYP2D6-selective dextromethorphan O-demethylation when CYP2C9 and CYP3A4 activities were suppressed (r = 0.97, P < 0.0001). Molecular modeling showed two predominant docking modes of celecoxib with CYP2D6, resulting in either a substrate or an inhibitor. A second allosteric binding antechamber, which stabilized the inhibition mode, was revealed. Modeling results were consistent with the observed substrate inhibition kinetics. Using HLMs from individual donors, the relative contribution of CYP2D6 to celecoxib metabolism was found to be highly variable and dependent on CYP2C9 genotypes, ranging from no contribution in extensive metabolizers with CYP2C9*1*1 genotype to approximately 30% in slow metabolizers with allelic variants CYP2C9*1*3 and CYP2C9*3*3. These results demonstrate that celecoxib may become a potential victim of CYP2D6-associated drug-drug interactions, particularly in individuals with reduced CYP2C9 activity. |
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| Keywords: | Celecoxib CYP2C9 CYP2D6 Drug-drug interaction Genetic polymorphism Hydroxy celecoxib |
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