Drug trafficking in mice: In vivo functions of OATP uptake and ABC efflux transporters

Abstract

In recent years, there has been increasing attention for drug uptake transporters of the Organic Anion-Transporting Polypeptide (human OATP, mouse Oatp, gene names SLCO, Slco) superfamily. Especially the OATP1A and OATP1B subfamilies turn out to have important physiological and pharmacological functions. Members of the OATP1A/1B subfamilies have received most interest because of their localization in tissues important for detoxification and pharmacokinetics (i.e. liver, small intestine and kidney) and their ability to mediate the cellular uptake of a wide variety of endogenous compounds but also many xenobiotics. OATP1A/1B transporters play important roles in the physiological detoxification by the liver of endogenous compounds, but also in determining tissue distribution, the rate and route of elimination, systemic exposure and oral bioavailability of drugs. In this thesis we studied OATP transporters in vivo using knockout mouse strains lacking all Oatp1a/1b transporters, and humanized transgenic mouse strains with liver-specific expression of human OATP1A2, OATP1B1 or OATP1B3. The concomitant use of these different mouse models is required because mouse and human OATP1A/1B proteins are not straightforward orthologues and their tissue localization and substrate specificity can differ substantially. Using these mice, we gained more insight into the physiological functions of OATP1A/1B, for instance the plasma clearance of unconjugated bilirubin and bile acids by facilitating their liver uptake. Further, we focussed on the pharmacological functions of these transporters in the plasma clearance (by efficient hepatic uptake) of statin drugs (pravastatin, rosuvastatin) and anticancer drugs (irinotecan/SN-38 and docetaxel). These findings have pharmacogenetic implications because there are several low-activity polymorphisms of OATP1A/1B transporters known. Also, complete deficiencies of either OATP1B1 or OATP1B3 transporters have been found in humans in addition to the Rotor syndrome patients, which completely lack both OATP1B1 and OATP1B3. All these individuals might be at risk of developing toxicities when treated with OATP1B substrates. Also co-administration of these drugs with OATP1A/1B inhibiting drugs might lead to clinically relevant drug-drug interactions. Human OATP1A/1B transporters are also expressed in several types of tumors and can thus confer sensitivity to anticancer drugs in cell lines overexpressing these transporters. Based on our findings that OATP1A/1B transporters transport several anticancer drugs in vivo we can speculate that they might mediate the tumor uptake of these anticancer drugs, and therefore modulate response to chemotherapy. We also studied the main ATP binding cassette (ABC) efflux transporters, ABCB1 (P-gp) and/or ABCG2 and their effect on the brain accumulation and oral bioavailability of tamoxifen and axitinib. We have found that endoxifen, a 100-fold more active metabolite of tamoxifen, is a P-gp substrate in vitro and in vivo. High expression of P-gp in breast tumors treated with tamoxifen might thus lead to insufficient intratumoral endoxifen concentrations and therefore insufficient therapeutic response. In the case of the tyrosine kinase inhibitor axitinib, we observed that Abcg2 has a role in limiting its bioavailability after oral administration, while at the blood-brain barrier, P-gp is the main determinant of axitinib brain penetration. These results might have clinical relevance for brain tumors positioned behind an intact and functional blood-brain barrier.