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.

Figure 1

Role of transporters affecting hepatic uptake and excretion of drugs and the interplay of hepatic transporters with phase I and phase II metabolism in the hepatic elimination of drugs. BCRP, breast cancer resistance protein; BSEP, bile salt export pump; MDR, multidrug resistance protein; MRP, multidrug resistance-associated protein; NTCP, sodium taurocholate co-transporting polypeptide; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; OCT, organic cation transporter.

Figure 2

Schematic representation of the secondary structure of human organic anion transporting polypeptide 1B1, depicting the positions of known amino acid exchanges. Reprinted from Kalliokoski, 2008 with permission of the copyright holder.

Figure 3

Mean plasma concentrations (A) and mean % decrease (±s.d.) in blood glucose 0–3 h (B) after ingestion of a single oral 0.5 mg dose of repaglinide in healthy participants with the SLCO1B1 c.521CC (n= 4, solid triangles), c.521TC (n= 12, solid circles), *1A/*1A (c.388AA-c521TT; n= 16, open circles) and *1B/*1B (c.388GG-c.521TT; n= 8, solid squares) genotypes. Modified from Kalliokoski et al., 2008a,;.