Impact of OATP transporters on pharmacokinetics

Abstract

Membrane transporters are now recognized as important determinants of the transmembrane passage of drugs. Organic anion transporting polypeptides (OATP) form a family of influx transporters expressed in various tissues important for pharmacokinetics. Of the 11 human OATP transporters, OATP1B1, OATP1B3 and OATP2B1 are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of their substrate drugs. OATP1A2 is expressed on the luminal membrane of small intestinal enterocytes and at the blood-brain barrier, potentially mediating drug transport at these sites. Several clinically used drugs have been identified as substrates of OATP transporters (e.g. many statins are substrates of OATP1B1). Some drugs may inhibit OATP transporters (e.g. cyclosporine) causing pharmacokinetic drug-drug interactions. Moreover, genetic variability in genes encoding OATP transporters can result in marked inter-individual differences in pharmacokinetics. For example, a single nucleotide polymorphism (c.521T > C, p.Val174Ala) in the SLCO1B1 gene encoding OATP1B1 decreases the ability of OATP1B1 to transport active simvastatin acid from portal circulation into the liver, resulting in markedly increased plasma concentrations of simvastatin acid and an enhanced risk of simvastatin-induced myopathy. SLCO1B1 polymorphism also affects the pharmacokinetics of many other, but not all (fluvastatin), statins and that of the antidiabetic drug repaglinide, the antihistamine fexofenadine and the endothelin A receptor antagonist atrasentan. This review compiles the current knowledge about the expression and function of human OATP transporters, their substrate and inhibitor specificities, as well as pharmacogenetics.

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

“…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.…”

“…sives inhibit OATP1B1 [12]. It is unlikely that this affected the results as serious illness was an exclusion criterion in WOSCOPS and the use of co-medication was probably low.…”

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…[175,176] OATP2B1 also quickly gained great attention when the family of OATP transporters was realized to influence drug pharmacokinetics. [10,177] Other transporters have only more recently been identified (e.g. OATP3A1 and OATP4A1) and thus their substrate and inhibitor affinity for pharmaceutical drugs is still unknown.…”

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

“…OATPs/Oatps facilitate sodiumindependent uptake transport of a wide variety of organic endoand exogenous compounds, such as bile acids, steroid and thyroid hormones and their conjugates, and numerous drugs and toxins (for overview, see refs. 3,4). Because of this broad substrate specificity and due to their expression in pharmacokinetically important tissues (liver, small intestine, kidney), OATPs/Oatps of the 1A/1a and 1B/1b subfamilies are thought to play an important role in drug disposition.…”