Association of carboxylesterase 1A genotypes with irinotecan pharmacokinetics in Japanese cancer patients.

British Journal of Clinical Pharmacology
Kimie SaiHaruhiro Okuda

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Association of UDP-glucuronosyltransferase 1A1 (UGT1A1) genetic polymorphisms *6 and *28 with reduced clearance of SN-38 and severe neutropenia in irinotecan therapy was demonstrated in Japanese cancer patients. * The detailed gene structure of CES1 has been characterized. * Possible functional SNPs in the promoter region have been reported. WHAT THIS STUDY ADDS * Association of functional CES1 gene number with AUC ratio [(SN-38 + SN-38G)/irinotecan], an in vivo index of CES activity, was observed in patients with irinotecan monotherapy. * No significant effects of major CES1 SNPs on irinotecan PK were detected. AIMS Human carboxylesterase 1 (CES1) hydrolyzes irinotecan to produce an active metabolite SN-38 in the liver. The human CES1 gene family consists of two functional genes, CES1A1 (1A1) and CES1A2 (1A2), which are located tail-to-tail on chromosome 16q13-q22.1 (CES1A2-1A1). The pseudogene CES1A3 (1A3) and a chimeric CES1A1 variant (var1A1) are also found as polymorphic isoforms of 1A2 and 1A1, respectively. In this study, roles of CES1 genotypes and major SNPs in irinotecan pharmacokinetics were investigated in Japanese cancer patients. METHODS CES1A diplotypes [combinations of ...Continue Reading

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Jun 8, 2012·European Journal of Clinical Pharmacology·Yuki SuzakiKyoichi Ohashi
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