Marked Alteration of Rosuvastatin Pharmacokinetics in Healthy Chinese with ABCG2 34G>A and 421C>A Homozygote or Compound Heterozygote

Abstract

Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor used to lower blood low-density lipoprotein cholesterol, 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 polymerase chain reaction-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 high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was carried out using the 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 with subjects with ABCG2 wild-type (c.34GG/421CC), plasma rosuvastatin C max and area under the curve, AUC 0-' , were significantly higher, while the apparent oral clearance, CL/F, was significantly lower in subjects with c.34AA, c.421AA, and c.34GA/ 421CA genotypes. Both t 1/2 and T max were similar among subjects with different genotypes. A high frequency of ABCG2 c.34G.A and c.421C.A variants was present in Chinese males, and the disposition of rosuvastatin was significantly affected by both variants. These data suggest that it is advisable to genotype these variants when prescribing rosuvastatin to Chinese subjects, leading to a precise dose for each individual.

The Effect of Genetic Polymorphisms in SLCO2B1 on the Lipid‐Lowering Efficacy of Rosuvastatin in Healthy Adults with Elevated Low‐Density Lipoprotein

“…We believe that a trough concentration measured at a single time-point does not fully reflect the overall systemic exposure of rosuvastatin. Our speculation is supported by the previous reports that ABCG2 c.421C>A (rs2231142), a well-known polymorphism to increase the systemic exposure of rosuvastatin [16,20,21], does not alter the trough level of rosuvastatin. Of note, compared to the other volunteers, one volunteer of SLCO1B1 *17/*17 genotype exhibited a much higher trough level of 18.8 lg/mL.…”

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia

“…37,[56][57][58][59][60] Increases in AUC by~160% were also demonstrated with ABCG2 rs2231137 A variants (p<0.001). 56 However, ABCB1 polymorphisms were not associated with alteration of any pharmacokinetic parameters in patients taking rosuvastatin therapy. 90 OATPs facilitate hepatic uptake of rosuvastatin, and two different variants in SLCO1B1 (rs2306283 and rs4149056) were associated with rosuvastatin pharmacokinetics.…”

“…Several studies have examined the effects of polymorphisms related to rosuvastatin pharmacokinetics; association between the ABCG2 rs2231142 A variant and changes in the pharmacokinetic parameters has been found . Increases in AUC by ~160% were also demonstrated with ABCG2 rs2231137 A variants (p<0.001) . However, ABCB1 polymorphisms were not associated with alteration of any pharmacokinetic parameters in patients taking rosuvastatin therapy .…”

Rosuvastatin Pharmacokinetics in Asian and White Subjects Wild Type for Both OATP1B1 and BCRP Under Control and Inhibited Conditions

“…When we digitally quantified the data presented in Fig.2a for AUC (0−t) in that paper 10 , median values for Chinese and Japanese were 62% and 35% higher, respectively, compared to Caucasians, versus the 11% difference we observed. In a recent study, Wan et al reported that ABCG2 c.34AA , with an allele frequency of 12.6% in Chinese, also has a significant effect on rosuvastatin pharmacokinetics in healthy Chinese subjects 25 , yielding a mean decrease of 34% in CL/F, although no change was observed for the heterozygous carrier of c.34GA. However, the volunteers here were not controlled for ABCG2 c.34 A>G SNP, since our clinical study preceded this publication.…”