Transporting pharmacogenomics into clinical practice

Abstract

A very interesting and concise study by Clarke et al. in this month’s issue of the Journal highlights important principles about the genetic determinants of drug disposition and toxicity, and the impact of underlying liver disease on adverse events from medications. The findings provide an opportunity to consider the current state of our knowledge about how genetic variations affect drug metabolism (i.e., pharmacogenomics), and to highlight efforts being developed to integrate genetic information into the clinical care of patients. The Clarke study is the most recent work in a series of publications by the authors examining the behavior of the hepatic uptake transporter organic ion transporting polypeptide-1B1 (OATP1B1) in drug disposition. This well-characterized membrane transporter regulates the uptake of organic compounds from the circulation into the hepatocyte where they can be metabolized. OATP1B1 has a large number of genetic variants, or single nucleotide polymorphisms (SNPs), that confer widely variable uptake activity by the transporter [1]; variants that confer reduced uptake lead to slower clearance of substrates, and therefore higher blood levels. That is exactly the case with several single nucleotide polymorphisms (SNPs) that have been linked to increased risk of myopathy associated with statin drugs used to treat hypercholesterolemia [1–3]. While statins are remarkably safe in general, individuals with these variants can be at up to 20 times greater risk of myopathy. Moreover, because these transporters have hundreds of substrates, altered activity can also lead to many adverse drug-drug interactions, in addition to altering the pharmacokinetics of individual drugs [1]. As hepatologists know well, many patients with hypercholesterolemia who are treated with statins are also obese and have metabolic syndrome complicated by non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). These conditions introduce the confounding effect of underlying fatty liver disease, which may further alter hepatic drug metabolism [4–6]. Additionally, the increased adiposemass in these patients can lead to accumulation of lipophilic drugs in fat cells and hepatocytes. The Clarke study examines how these two important variables, namely the genetic regulation of OATP1B1 activity and