Investigators from the Chinese University of Hong Kong recently described how polymorphisms in the gene coding for ATP-binding cassette G2 (ABCG2) – a membrane transporter found in hepatocytes – influence the pharmacokinetics of the lipid-lowering agent rosuvastatin. Speaking at a WCC 2010 special session organized by the Hong Kong College of Cardiology and the Macau Cardiology Association, principal investigator Professor Brian Tomlinson reported that individuals with the c.421AA genotype showed a 6.9% greater reduction in low-density lipoprotein-cholesterol (LDL-C) with rosuvastatin intake compared with subjects with the c.421CC genotype.
Membrane transporters are now recognized as important determinants of the passage of drugs intracellularly and extracellularly. These polypeptides are expressed in various tissues, such as the liver and small intestine, and help regulate drug transport at these sites. Variations in genes encoding for hepatocyte membrane transporters may result in marked inter-individual differences in statin pharmacokinetics.
“Rosuvastatin is known to have higher plasma concentrations in Asians, and the prescribing advice recognizes this from the start and suggests using smaller doses in Asians,” said Professor Tomlinson. “We now know that it is the ABCG2 polymorphism that is responsible for these higher blood levels.”
Investigators evaluated 305 Chinese patients with hypercholesterolemia seen at the Prince of Wales Hospital who were treated with rosuvastatin 10 mg daily. Patients with the c.421AA polymorphism were found to have a greater reduction in LDL-C level with treatment, in a gene-dose-dependent manner. “These individuals have higher rosuvastatin blood levels, and consequently experience a greater drug effect – equivalent to the effect obtained by doubling the dose of the drug,” Tomlinson explained.
Polymorphisms of other membrane transporter genes have been shown to similarly impact the pharmacokinetics of other statins. Polymorphisms in the SLCO1B1 gene encoding the influx transporter OATP1B1 – expressed on the sinusoidal membrane of hepatocytes and shown to regulate the hepatic uptake of statins – have been demonstrated in a recent genome-wide association study to be strongly associated with simvastatin-induced myopathy. The SLCO1B1 polymorphism leads to a decreased ability of OATP1B1 to transport active simvastatin from the portal circulation into the liver, resulting in markedly increased drug plasma concentrations and an elevated risk of statin-induced myopathy.  |
