Hepatic OATP and OCT uptake transporters: their role for drug-drug interactions and pharmacogenetic aspects

Abstract

Uptake transporters in the basolateral membrane of hepatocytes are important for the hepatobiliary elimination of drugs. Further, since drug-metabolizing enzymes are located intracellularly, uptake into hepatocytes is a prerequisite for their subsequent metabolism. Therefore, alteration of uptake transporter function (e.g., by concomitantly administered drugs or due to functional consequences of genetic variations, leading to reduced transport function) may result in a change in drug pharmacokinetics. In this review, we focus on the hepatocellularly expressed members of the OATP and OCT family, their impact on transport-mediated drug-drug interactions, and on the functional consequences of variations in genes encoding these transporters.

Role of Organic Anion-Transporting Polypeptides for Cellular Mesalazine (5-Aminosalicylic Acid) Uptake

“…An important mechanism of drug-drug interactions is inhibition of drug uptake by a second, concomitantly administered drug (for review, see Fahrmayr et al, 2010). Because we were able to show that mesalazine is a substrate of OATP1B1, OATP1B3, and OATP2B1, we determined the impact of drugs known to inhibit OATPs and of other drugs used for treatment of inflammatory bowel disease on OATP1B1-, OATP1B3-, and OATP2B1-mediated mesalazine uptake.…”

“…Our data indicate that mesalazine delivered from the portal venous blood to the liver will be taken up by OATP1B1, OATP1B3, and OATP2B1 localized in the basolateral membrane of hepatocytes (K m values 55.1, 77.4, and 188.9 M, respectively). Genetic variations in the SLCO1B1 gene encoding for mutated OATP1B1 proteins, in particular the variants SLCO1B1*5 and *15, affect the plasma concentrations, therapeutic effects, and side effects of a broad variety of drugs, including statins and certain oral antidiabetic drugs (Fahrmayr et al, 2010). For example, recent studies reported a strong dependence of simvastatin acid plasma concentrations on the SLCO1B1 genotype (Pasanen et al, 2006) and a clear relationship between SLCO1B1 variants and the risk for statin-induced myopathy (Link et al, 2008).…”

“…OATPs transport a broad spectrum of endogenous compounds and drugs (Fahrmayr et al, 2010). OATP1B1, OATP1B3, and OATP2B1 are the three major hepatic OATPs mediating uptake of their substrates from the portal venous blood into the hepatocytes.…”

“…OATP1B1, OATP1B3, and OATP2B1 are the three major hepatic OATPs mediating uptake of their substrates from the portal venous blood into the hepatocytes. Genetically determined variations in the SLCO1B1 gene affecting OATP1B1 function (e.g., SLCO1B1*1b, *5, and *15) have a major impact on the plasma concentrations, therapeutic effects, and side effects of multiple drugs including HMG-CoA reductase inhibitors (Marzolini et al, 2004;Link et al, 2008;Fahrmayr et al, 2010;Niemi, 2010). Moreover, inhibition of specific uptake transporters by concomitantly administered drugs is an important mechanism of drugdrug interactions (for review see Kindla et al, 2009;Fahrmayr et al, 2010).…”

“…Uptake transporters such as members of the organic anion-transporting polypeptide family (OATPs) (gene symbol SLCO), which are located in the luminal membrane of enterocytes and in the basolateral membrane of hepatocytes, are well recognized determinants of drug absorption, distribution, and effects (Nies et al, 2009;Fahrmayr et al, 2010). OATPs transport a broad spectrum of endogenous compounds and drugs (Fahrmayr et al, 2010).…”