A new CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride inhumans

(+)-Cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502 ) is a newly developed drug as a platelet-activating factor receptor antago nist. The disposition of SM-12502 was investigated in plasma from 28 health y Japanese volunteers after a single i.v. administration of SM-12502. Three of 28 subjects were phenotyped as poor metabolizers (PMs). Genomic DNAs fr om three extensive metabolizers or three PMs of SM-12502 were analyzed by S outhern blot analysis with CYP2A6 cDNA as a probe. DNAs from three PMs dige sted with Sad and Sphl showed novel restriction fragment length polymorphis ms (RFLPs); one type without 4.5- and 2.6-kb fragments and a weak density o f a 6.4-kb fragment (E-type), and the other type without 7.1- and 5.5-kb re striction fragments (C'-type) as compared with three extensive metabolizers , respectively. The deletional restriction fragments specific to three PMs in Sacl- and Sphl-RFLPs were identified as CYP2A6. Using polymerase chain r eaction-RFLP analyses of the gene from the three PMs, we found that the exo n 1, exon 8, and exon 9 in CYP2A6 were absent. A new RFLP characterized by Sad and Sphl was found to be due to the entire gene deletion of the three e xons and was associated with the decreased metabolism of SM-12502. This stu dy demonstrates a new deletional allele in the human CYP2A6 gene responsibl e for the poor metabolic phenotype of SM-12502.