Abstract
(+)-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 CYP2A6gene responsible for the poor metabolic phenotype of SM-12502.
Footnotes
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Send reprint requests to: Dr. Tetsuya Kamataki, Ph.D., Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, N12W6, Sapporo 060 Japan. E-mail:kamataki{at}pharm.hokudai.ac.jp
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↵1 This study was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan.
- Abbreviations:
- AUC
- area under the plasma concentration-time curve
- CYP
- cytochrome P-450
- EM
- extensive metabolizer
- PCR
- polymerase chain reaction
- PM
- poor metabolizer
- RFLP
- restriction fragment length polymorphism
- SM-12502
- (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride
- Received April 21, 1998.
- Accepted December 6, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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