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
Binbin Xia
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
Xianjun Liu
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
Yali Li
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
Yang Liu
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
Wenfang Sun
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
Jing Chen
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
Liushui Li
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
Jingyao Pang
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
Shicai Chen
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
Hua Cheng *
Department of Pharmacy, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, P.R. China.
*Author to whom correspondence should be addressed.
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.
Keywords: Genetic polymorphism, SLCO1B1 388A＞G, SLCO1B1 521T＞C, CYP3A4 1*B, CYP3A4 1*G, CYP3A5*3, pharmacokinetics, atorvastatin calcium