Prediction of inter-individual variability in pharmacokinetics of CYP2C19 substrates in humans
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- CHIBA Koji
- Laboratory of Clinical Pharmacology, Yokohama College of Pharmacy Department of Drug Development Science & Clinical Evaluation, Faculty of Pharmacy, Keio University Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN
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- SHIMIZU Keiko
- Kyorin Pharmaceutical Co., Ltd.
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- KATO Motohiro
- Chugai Pharmaceutical Co., Ltd.
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- NISHIBAYASHI Takaaki
- Department of Drug Development Science & Clinical Evaluation, Faculty of Pharmacy, Keio University
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- TERADA Kazuki
- Laboratory of Clinical Pharmacology, Yokohama College of Pharmacy
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- IZUMO Nobuo
- Laboratory of Clinical Pharmacology, Yokohama College of Pharmacy
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- SUGIYAMA Yuichi
- Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN
書誌事項
- タイトル別名
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- Prediction of Inter-individual Variability in the Pharmacokinetics of CYP2C19 Substrates in Humans
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説明
Significant inter-individual variability of exposure for CYP2C19 substrates may be only partly due to genetic polymorphism. Therefore, the in vivo inter-individual variability in hepatic intrinsic clearance (CLint,h) of CYP2C19 substrates was estimated from reported AUC values using Monte Carlo simulations. The coefficient of variation (CV) for CLint,h in poor metabolizers (PM) expected from genotypes CYP2C19*2/*2, CYP2C19*3/*3 or CYP2C19*2/*3 was estimated as 25.8% from the CV for AUC of omeprazole in PMs. With this, CVs of CLint,h in extensive metabolizers (EM: CYP2C19*1/*1), intermediate metabolizers (IM: CYP2C19*1/*2 or *3) and ultra-rapid metabolizers (UM), CYP2C19*17/*17 and *1/*17, were estimated as 66.0%, 55.8%, 6.8% and 48.0%, respectively. To validate these CVs, variability in the AUC of CYP2C19 substrates lansoprazole and rabeprazole, partially metabolized by CYP3A4 in EMs and IMs, were simulated using the CV in CLint,h for CYP2C19 EMs and IMs and 33% of the CV previously reported for CYP3A4. Published values were within 2.5–97.5 percentile range of simulated CVs for the AUC. Furthermore, simulated CVs for the AUC of omeprazole and lansoprazole in ungenotyped populations were comparable with published values. Thus, estimated CLint,h variability can predict variability in the AUC of drugs metabolized not only by CYP2C19 but also by multiple enzymes.
収録刊行物
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- Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ
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Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 29 (5), 379-386, 2014
日本薬物動態学会