GENETIC-POLYMORPHISM OF CYP2C19 AND LANSOPRAZOLE PHARMACOKINETICS IN JAPANESE SUBJECTS

Objective: We investigated whether interindividual differences in the pharmacokinetic disposition of lansoprazole are attributed to the gene tic polymorphism of CYP2C19 which occurred by two mutations, CYP2C19m1 and CYP2C19m2, in 20 Japanese subjects. Methods: Polymerase chain rea ction (PCR) restriction fragment length polymorphism procedures were u sed to detect the CYP2C19m1 mutation in exon 5 and the CYP2C19m2 mutat ion in exon 4 using SmaI and BamHI, respectively. Results: Ten subject s were homozygous (wt/wt subjects) for the wt allele in both exon 5 an d exon 4, four subjects were heterozygous (wt/m1) for the CYP2C19m1 mu tation, and two subjects were heterozygous (wt/m2) for the CYP2C19m2. The remaining four subjects had both mutated alleles in CYP2C19 genes, i.e., two were homozygous (m1/m1) for the defect in exon 5 and two we re heterozygous (m1/m2) for the two defects in exons 5 and 4. The subj ects in group 1 (wt/wt, wt/m1 and wt/m2) were the extensive metabolize rs (EMs) for 5-hydroxylation of lansoprazole and were in the range of hydroxylation indexes from 3.83 to 19.8, whereas the subjects in group 2 (m1/m1 and m1/m2) were the poor metabolizers (PMs) and the indexes were in the range of 38.5 to 47.6. In group 2, AUC, t(1/2) and CL/f of lansoprazole were significantly greater, longer, and lower, respectiv ely, than those in group 1. Conclusion: The hydroxylation of lansopraz ole to 5-hydroxylansoprazole was apparently impaired in the subjects w ith the genetic defects of CYP2C19 (m1/m1 or m1/m2).