Influence of cytochrom P450 CYP2C9 polymorphism on the pharmacokinetics of tolbutamide metabolism using oligonucleotide genotyping microarray

AimTo investigate the influence of cytochrom P450 CYP2C9 polymorphism on the pharmacokinetics of tolbutamide. MethodsAn oligonucleotide microarray was designed and fabricated to genotype the CYP2C9 accurately and quickly. 137 healthy volunteers were genotyped with the array to investigate the frequency of CYP2C9 functional SNPs. Moreover, 1 homozygous mutant, 9 heterozygous and 10 wild-genotypes subjects in the assay were selected randomly and sequenced directly. After orally taking tolbutamide, blood samples and urine samples were collected, and their pharmacokinetics was studied with HPLC. ResultsCYP2C9*1/*3 were found in 9 of 137 volunteers, CYP2C9*3/*3 in only one, others were all CYP2C9*1/*1 wild types. CYP2C9*2, CYP2C9*4 and CYP2C9*5 alleles were not detected. Direct sequencing of the purified PCR products of the heterozygotes, mutant homozygotes and ten wild type individuals gave a corresponding result to that genotyped by microarray. Pharmacokinetic outcome showed that the individuals with CYP2C9*1/*3 or CYP2C9*3/*3 had slower metabolic elimination of tolbutamide than those with CYP2C9*1/*1. ConclusionCYP2C9 genetic polymorphism has a significant influence on the pharmacokinetics of tolbutamide. Pharmacogenomic study will be helpful in guiding rational and individualized medication.