Anti-cancer drug disposition: In vitro and in vivo functions of ABC efflux and OATP uptake transporters

Abstract

ATP-binding cassette (ABC) efflux and Organic Anion-Transporting Polypeptide (OATP) uptake transporters are two major membrane transporter superfamilies that have major roles in the absorption, disposition and toxicity of drugs. They are widely expressed in several pharmacokinetically relevant organs (e.g. liver, small intestine, brain and kidney) and affect pharmacokinetics of a broad range of drugs including many chemotherapeutics. In this thesis, we have investigated the in vitro and in vivo pharmacological functions of ABC and OATP transporters for several anti-cancer drugs. To do this, we have used various cell systems overexpressing various transporters and knockout and humanized transgenic mouse models. We demonstrated that ABC transporters Abcb1a/1b (P-gp) and Abcg2 (Bcrp1) restrict the oral absorption and/or brain disposition of tyrosine kinase inhibitors vemurafenib, CYT387 and regorafenib, and poly ADP-ribose polymerase inhibitor rucaparib. Pharmacological inhibition of these transporters by a dual inhibitor, elacridar, significantly improved the systemic and brain levels of vemurafenib, suggesting a possibility for enhancing efficacy of vemurafenib in cancer patients with brain metastases. Our studies also found that mouse and human OATP1A/1B transporters are important in plasma clearance and liver uptake of the anti-cancer drug doxorubicin, an atypical OATP substrate due to its structure. Furthermore, using combinations of methotrexate (anti-cancer drug) with rifampicin (antibiotic) or telmisartan (hypertension drug), we showed that humanized transgenic mice with liver specific expression of human OATP1B1 and -1B3 are useful models to assess drug-drug interactions mediated by these transporters in vivo. Moreover, our studies revealed that Oatp1a/1b and Abcc3 (Mrp3) transporters together contribute to the liver elimination of a glucuronidated conjugate of the anti-cancer drug sorafenib. This liver detoxification could be described by ‘hepatocyte hopping’ which is recently introduced using an endogenous substrate, bilirubin glucuronide. As sorafenib-glucuronide is the first exogenous substrate shown to be subjected to this process, our findings suggest a broader pharmacological relevance for ‘hepatocyte hopping’. With these studies, we have clearly shown that ABC and OATP drug transporters are important in the pharmacokinetics (e.g. oral availability, and liver and brain disposition) of a wide range of anti-cancer drugs, which can be used as a solid translational basis for clinical studies in several cases.