Influence of cytochrom P450 CYP2C9 polymorphism on the pharmacokinetics of tolbutamide metabolism using oligonucleotide genotyping microarray / 药学学报

ABSTRACT

<p><b>AIM</b>To investigate the influence of cytochrom P450 CYP2C9 polymorphism on the pharmacokinetics of tolbutamide.</p><p><b>METHODS</b>An 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.</p><p><b>RESULTS</b>CYP2C9 *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.</p><p><b>CONCLUSION</b>CYP2C9 genetic polymorphism has a significant influence on the pharmacokinetics of tolbutamide. Pharmacogenomic study will be helpful in guiding rational and individualized medication. Key words tolbutamide; cytochrom P450 CYP2C9; allele; single nucleotide polymorphism; genotyping</p>