RT Journal Article
SR Electronic
T1 Marked Alternation of Rosuvastatin Pharmacokinetics in Healthy Chinese with ABCG2 34G＞A and 421C＞A Homozygote or Compound Heterozygote
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.115.225045
DO 10.1124/jpet.115.225045
A1 Zirui Wan
A1 GUO WANG
A1 Tailin Li
A1 Biaobo Xu
A1 Qi Pei
A1 Yan Peng
A1 Hong Sun
A1 Lijuan Cheng
A1 Ying Zeng
A1 Guoping Yang
A1 Yuan-Shan Zhu
YR 2015
UL http://jpet.aspetjournals.org/content/early/2015/06/16/jpet.115.225045.abstract
AB Rosuvastatin, a HMG-CoA reductase inhibitor used to lower blood LDL-C, is a substrate of the membrane ABCG2 exporter. ABCG2 variants have been shown to alter rosuvastatin disposition. The objective of this study is to determine the impact of ABCG2 34/421 compound haplotypes on rosuvastatin pharmacokinetics in healthy Chinese volunteer subjects. Eight-hundred healthy Chinese males were genotyped by PCR-Pyrosequencing for ABCG2 34G>A, ABCG2 421C>A, SLCO1B1 521T>C and CYP2C9*3 variants. Sixty-two male subjects with wild-type SLCO1B1 c.521TT and CYP2C9*3 were recruited for this pharmacokinetic study of rosuvastatin. A single oral dose of 10 mg rosuvastatin was administrated to each subject, and blood samples were collected before and at various time points after drug administration. Plasma concentration of rosuvastatin was determined by HPLC-MS/MS, and pharmacokinetic analysis was carried out using WinNonlin program. In Chinese males, high allele frequency of ABCG2 c.34G>A (0.275) and c.421C>A (0.282) was observed, resulting in a considerable portion (23.3%) of subjects being ABCG2 34/421 compound heterozygotes. Compared to subjects with ABCG2 wild-type (c.34GG/421CC), plasma rosuvastatin Cmax and AUC0-∞ were significantly higher, while CL/F was significantly lower in subjects with c.34AA, c.421AA, and c.34GA/421CA genotypes. Both T1/2 and Tmax were similar among subjects with different genotypes. A high frequency of ABCG2 c.34G>A and c.421C>A variants were present in Chinese males, and the disposition of rosuvastatin was significantly affected by both variants. This data suggests that it is advisable to genotype these variants when prescribing rosuvastatin to Chinese subjects, leading to a precise dose for each individual.