The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

Abstract

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are well established in the treatment of hypercholesterolaemia and the prevention of coronary artery disease. Despite this, there is wide interindividual variability in response to statin therapy, in terms of both lipidlowering and adverse drug reactions. The major site of statin action is within hepatocytes and recent interest has focussed on genetic variation in hepatic influx and efflux transporters for their potential to explain these differences. In this review we explore current literature regarding the pharmacokinetic and pharmacodynamic influence of the common c.388A4G and c.521T4C single-nucleotide polymorphisms (SNPs) within the solute carrier organic anion transporter 1B1 (SLCO1B1) gene, encoding the organic anion transporter polypeptide 1B1 (OATP1B1) influx transporter. We discuss their potential to predict the efficacy of statin therapy and the likelihood that patients will experience adverse effects.

The effects of a single nucleotide polymorphism in SLCO1B1 on the pharmacodynamics of pravastatin

“…A recently published physiology-based pharmacokinetic model of pravastatin predicted that variants of OATP1B1 with reduced transporter activity will have a large effect on the plasma AUC but only a minimal effect on the liver AUC [11]. This is consistent with our findings, as it is the liver AUC that governs the lipid-lowering response, and this is the likely explanation for the lack of effect of rs4149056 on pravastatin pharmacodynamics, even though an effect on pravastatin plasma concentrations is well established [1].…”

“…Analyses of pravastatin pharmacokinetics consistently show rs4149056 to be responsible for most of the difference between SLCO1B1 haplotypes [1,12]. Moreover, rs2306283 had only half the effect of rs4149056 on the LDL response to simvastatin in the SEARCH study [2].Although there may be larger differences between rare haplotypes containing multiple SNPs, the inevitable reduction in the number of participants in each group means the differences are unlikely to be statistically significant unless a larger study is performed.…”

“…The C-allele of rs4149056 encodes a reduced activity variant of OATP1B1 with a valine to alanine substitution at position 174. Carriers of the rs4149056 SNP develop a significantly higher plasma area under the concentration-time curve (AUC) than noncarriers after dosing with pravastatin, atorvastatin, rosuvastatin and simvastatin [1].…”

“…The hepatic anion transporter OATP1B1 encoded by the gene SLCO1B1 facilitates the entry of statins along with a variety of other drugs and endogenous anions into hepatocytes [1]. Statins target HMG-CoA reductase in the liver and are largely excreted in the bile so entry into hepatocytes is required for both their action and excretion.…”

Pharmacology

“…The effect of statins depends on the statin concentration at the site of action, the liver. This concentration can be altered by several factors, like diet and concomitant medication (Romaine et al, 2010). Muscle symptoms are a common problem during statin use ranging from mild myalgia to severe rhabdomyolysis (Law & Rudnicka, 2006).…”