Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption

Abstract

Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood-brain barrier of drugs, respectively. To understand the importance of OATPs in the hepatic clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, hepatic uptake clearance rather than metabolic intrinsic clearance is the more important determinant of hepatic clearances. The importance of the unbound concentration ratio (liver/blood), K p,uu , of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC 50 of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug-drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful.

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

“…60) Shitara et al tried to simultaneously estimate the contribution of OATP1B1 to the overall hepatic uptake of OATP substrate drugs and decreased function of OATP1B1 by c.521T>C mutation in humans based on previous clinical pharmacogenetic studies. 61) In this approach, since hepatic intrinsic clearance is proportional to the intrinsic uptake clearance following the pharmacokinetic theory, the ratio of hepatic intrinsic clearance of each substrate drug in subjects with 521CC to that in subjects with 521TT was first estimated based on the reported AUC increase of the drug by c.521T>C mutation. This ratio can be expressed as shown below.…”

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

“…Organic Anion Transporting Polypeptide (OATP) 1B1 and OATP1B3 mediate hepatic uptake and govern the elimination of many clinically used drugs such as rosuvastatin, atorvastatin, and repaglinide (Niemi et al, 2011, Shitara et al, 2013. Hence, inhibitory drug-drug interactions (DDIs) with OATP1B have broad implications with respect to drug efficacy, safety, and labeling of a new molecular entity (NME).…”

Effect of OATP-binding on the prediction of biliary excretion

“…It has been cited in the literature that presence of OATPs in the hepatocytes may indicate their significance in biliary excretion process (Shitara et al, 2013;Fenner et al, 2012). There has been some evidence from structure-activity studies that indicate similar structural features for OATP substrates and those with high biliary excretion (Varma et al, 2012).…”