Plasma membrane transporters, located on epithelial cells of many tissues, eg, intestinal, renal, and hepatic membranes, mediate selective uptake and efflux of endogenous compounds and xenobiotics including many drug products. Transporters, which often work in concert with drug-metabolizing enzymes, play important roles in determining plasma and tissue concentrations of drugs and their metabolites. Genetic differences in transporter genes can dramatically alter drug disposition and response and thus may increase risk for toxicities. In this section, a key example of a polymorphic uptake transporter and its pharmacologic impact on statin toxicity are described.
The OATP1B1 transporter (encoded by the SLCO1B1 gene) is located on the sinusoidal membrane (facing the blood) of hepatocytes and is responsible for the hepatic uptake of mainly weakly acidic drugs and endogenous compounds, eg, statins, methotrexate, and bilirubin. Over 40 nonsynonymous variants (nsSNPs) have been identified in this transporter, some of which result in decreased transport function. A common reduced function polymorphism, rs4149056, has been shown to reduce transport of OATP1B1 substrates in vitro as well as to alter pharmacokinetic and clinical outcomes in vivo. The variant results in an amino acid change, Val174Ala, and is associated with reduced membrane expression, likely as a result of impaired trafficking capability. Allele *5 is relatively rare (rs4149056 alone; ∼1%), but various other reduced function alleles (*15 and *17; haplotypes containing rs4149056) are common in most European and Asian populations (between 5% and 15%) (Table 5–1).
Example: HMG-coenzyme A (CoA) reductase inhibitors (statins) are highly effective medications that are widely prescribed to reduce serum lipids for the prevention of cardiovascular events (Chapter 35). Seven statins in use currently are generally safe and well-tolerated, but skeletal muscle toxicity can limit their use. Known risk factors include high statin dose, interacting medications, advanced age, and metabolic comorbidities. Furthermore, the common variant, rs4149056 in SLCO1B1, increases systemic exposure of simvastatin (221% increase in plasma area under the curve for patients homozygous for the rs4149056 variant, eg, SLCO1B1*5/*5; *5/[*15 or *17]; or [*15 or *17]/[*15 or *17]) and was identified to have the single strongest association with simvastatin-induced myopathy in a GWA analysis. For individuals receiving simvastatin with reduced OATP1B1 function (at least one nonfunctional allele), CPIC recommends a lower simvastatin dose or an alternative statin (Table 5–2).
BREAST CANCER RESISTANCE PROTEIN (BCRP, ABCG2)