The Chinese-Han Population Carrying Wild-type Genotypes of SLCO1B1 388A>G, SLCO1B1 521T>C, CYP3A4 1B, CYP3A4 1G, and CYP3A5*3 Exhibits a Significant Alteration in the Pharmacokinetics of Atorvastatin Calcium

Abstract

Due to the diverse genetic characteristics of metabolism and high drug plasma exposure, great inter-subject variability exists in the clinical efficacy and incidence of adverse events. This study aimed to evaluate the associations between the SLCO1B1 388A＞G (rs2306283) polymorphism and the pharmacokinetics of atorvastatin calcium (AC) in healthy volunteers who carried the wild genotypes of SLCO1B1 521T＞C (rs4149056), CYP3A4 1B (rs2740574), CYP3A4 1G (rs2242480), and CYP3A5*3 (rs776746). A FISH technique was employed to investigate the genetic polymorphisms in 187 healthy male volunteers. The pharmacokinetic study was conducted on a group of healthy male Chinese-Han volunteers with wild-type genotypes of SLCO1B1 521T>C, CYP3A4 1B, CYP3A41G and CYP3A53 genes, consisting of either mutant heterozygotes (n=10) or mutant homozygotes (n=10) of SLCO1B1 388A>G. The results were then compared to the pharmacokinetic parameters of AC in subjects with the wild-type genotype of SLCO1B1 388A>G, as previously described. Based on the distribution of genotypes, the 187 volunteers could be divided into 28 groups. The top 10 groups accounted for nearly 85% of the total volunteers. No significant differences (P>0.05) were observed in the pharmacokinetic parameters between subjects carrying homozygous and heterozygous genotypes of SLCO1B1 388A>G. However, The Cmax of subjects carrying the wild-type genotype of SLCO1B1 388A＞G was about 14.75 times higher than that of the heterozygous genotype group and 10.43 times higher than that of the homozygous genotype group. The AUC0-72h of volunteers with the wild-type genotype of SLCO1B1 388A＞G was about 13.81 times higher than that of the heterozygous genotype group and 11.96 times higher than that of the homozygous genotype group. Volunteers carrying wild genotypes of SLCO1B1 388A＞G, SLCO1B1 521T＞C, CYP3A4 1B, CYP3A4 1G, and CYP3A5*3 showed significantly higher levels of Cmax and AUC (P<0.01), as well as markedly decreased values of CLz/F and Vz/F (P<0.01) of AC. In conclusion, patients carrying the wild genotype of SLCO1B1 388A>G, SLCO1B1 521T>C, CYP3A41G, CYP3A41B, and CYP3A5*3 should receive a lower dose of AC to minimize the risk of adverse effects.