ABCG2 Polymorphism Is Associated With the Low-Density Lipoprotein Cholesterol Response to Rosuvastatin

Abstract

The ATP-binding cassette G2 (ABCG2) c.421C>A (rs2231142) polymorphism influences the pharmacokinetics of rosuvastatin. We examined whether this polymorphism influences the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of the drug. In 305 Chinese patients with hypercholesterolemia who were treated with rosuvastatin at a dosage of 10 mg daily, the c.421A variant was found to be significantly associated with greater reduction in LDL-C level, in a gene-dose-dependent manner. As compared with subjects with the c.421CC genotype, those with the c.421AA genotype showed a 6.9% greater reduction in LDL-C level, which would be equivalent to the effect obtained by doubling the dose of rosuvastatin.

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

“…Furthermore, a population-based survey showed an influence of genetic variants in the efflux transporter ABCB1 genotype on simvastatin efficacy in men by showing that previously identified SNPs are associated with larger reduction of lipid parameters than carriers of the wild-type haplotype [43]. Similarly, Tomlinson et al [44] reported a significant effect of genetic variants of the ABCG2 transporter in a patient cohort treated with rosuvastatin. In summary, the present work confirms our hypothesis of intrahepatic drug effects as assessed by reaching treatment goals being dependent on the genetic makeup of hepatocellular uptake transport.…”

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

“…Therefore, RSV CL Uptake likely is underestimated in rat SCH (Table 1); in contrast, OATP-mediated CL Uptake in human SCH appears to be maintained over days in culture (Kotani et al, 2011). Bcrp and Mrp2 expression have been reported to increase and decrease, respectively, in rat SCH compared with liver tissue (Li et al, 2009a(Li et al, ,b, 2010. Therefore, the effects of these changes may have minimal overall impact on RSV CL Bile .…”

“…Hepatic basolateral efflux of RSV could be clinically relevant because impaired hepatic transport resulting from drug-drug interactions and genetic polymorphisms has been shown to alter the pharmacokinetics of RSV Simonson et al, 2004;Zhang et al, 2006;Kiser et al, 2008;Kitamura et al, 2008;Keskitalo et al, 2009;Hobbs et al, 2012). Some of these changes have been associated with altered efficacy (i.e., lowering of low-density lipoprotein) of RSV (Simonson et al, 2003;Tomlinson et al, 2010), and increased systemic exposure has been associated with life-threatening rhabdomyolysis, which is related to statin use in general (Hamilton-Craig, 2001; Thompson et al, 2003). Candidate basolateral efflux transporters for RSV include MRP3 and This study was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01GM41935].…”

Statin Muscle Toxicity and Genetic Risk Factors

“…This observation is probably explained by the higher blood concentration of this statin, which increased the myopathy risk observed in Asians [42]. All of these results demonstrate that there may be a strong genetic susceptibility to both myopathy and statin-induced myalgias in the absence of elevated CPK values.…”

“…Tomlinson et al [42] in a recent study of 305 Chinese patients treated with rosuvastatin, reported a significant greater reduction in LDL-C levels associated with the presence of a c.421CC genotype. This observation is probably explained by the higher blood concentration of this statin, which increased the myopathy risk observed in Asians [42].…”