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Vol. 289, Issue 1, 437-442, April 1999

A New CYP2A6 Gene Deletion Responsible for the In Vivo Polymorphic Metabolism of (+)-cis-3,5-Dimethyl-2-(3-pyridyl)thiazolidin-4-one Hydrochloride in Humans1

Ken-Ichi Nunoya, Tsuyoshi Yokoi, Kanzo Kimura, Tadashi Kainuma, Kunio Satoh, Moritoshi Kinoshita and Tetsuya Kamataki

Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan (K. Nu., T.Y., T. Kam.); Clinical Research and Development Division, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan (K.K.); Kouseikai-Kinen Hospital, Suita, Japan (T. Kai); Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan (K.S.); and Diagnostics Division, Otsuka Assay Laboratories, Otsuka Pharmaceuticals Co., Ltd., Tokushima, Japan (M.K.)

(+)-Cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) is a newly developed drug as a platelet-activating factor receptor antagonist. The disposition of SM-12502 was investigated in plasma from 28 healthy Japanese volunteers after a single i.v. administration of SM-12502. Three of 28 subjects were phenotyped as poor metabolizers (PMs). Genomic DNAs from three extensive metabolizers or three PMs of SM-12502 were analyzed by Southern blot analysis with CYP2A6 cDNA as a probe. DNAs from three PMs digested with SacI and SphI showed novel restriction fragment length polymorphisms (RFLPs); one type without 4.5- and 2.6-kb fragments and a weak density of a 6.4-kb fragment (E-type), and the other type without 7.1- and 5.5-kb restriction fragments (C'-type) as compared with three extensive metabolizers, respectively. The deletional restriction fragments specific to three PMs in SacI- and SphI-RFLPs were identified as CYP2A6. Using polymerase chain reaction-RFLP analyses of the gene from the three PMs, we found that the exon 1, exon 8, and exon 9 in CYP2A6 were absent. A new RFLP characterized by SacI and SphI was found to be due to the entire gene deletion of the three exons and was associated with the decreased metabolism of SM-12502. This study demonstrates a new deletional allele in the human CYP2A6 gene responsible for the poor metabolic phenotype of SM-12502.

0022-3565/99/2891-0437$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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