title: The impact of Organic Anion-Transporting Polypeptides (OATPs) on disposition and toxicity of antitumor drugs: Insights from knockout and humanized mice.
abstract: It is now widely accepted that organic anion-transporting polypeptides (OATPs), especially members of the OATP1A/1B family, can have a major impact on the disposition and elimination of a variety of endogenous molecules and drugs. Owing to their prominent expression in the sinusoidal plasma membrane of hepatocytes, OATP1B1 and OATP1B3 play key roles in the hepatic uptake and plasma clearance of a multitude of structurally diverse anti-cancer and other drugs. Here, we present a thorough assessment of the currently available OATP1A and OATP1B knockout and transgenic mouse models as key tools to study OATP functions in vivo. We discuss recent studies using these models demonstrating the importance of OATPs, primarily in the plasma and hepatic clearance of anticancer drugs such as taxanes, irinotecan/SN-38, methotrexate, doxorubicin, and platinum compounds. We further discuss recent work on OATP-mediated drug-drug interactions in these mouse models, as well as on the role of OATP1A/1B proteins in the phenomenon of hepatocyte hopping, an efficient and flexible way of liver detoxification for both endogenous and exogenous substrates. Interestingly, glucuronide conjugates of both the heme breakdown product bilirubin and the protein tyrosine kinase-targeted anticancer drug sorafenib are strongly affected by this process. The clinical relevance of variation in OATP1A/1B activity in patients has been previously revealed by the effects of polymorphic variants and drug-drug interactions on drug toxicity. The development of in vivo tools to study OATP1A/1B functions has greatly advanced our mechanistic understanding of their functional role in drug pharmacokinetics, and their implications for therapeutic efficacy and toxic side effects of anticancer and other drug treatments.
authors.affiliation: Bilkent University, Department of Molecular Biology and Genetics, 06800 Bilkent, Ankara, Turkey.
authors.forename: Selvi
authors.initials: S
authors.lastname: Durmus
authors.affiliation: The Netherlands Cancer Institute, Division of Molecular Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: van Hoppe
authors.affiliation: The Netherlands Cancer Institute, Division of Molecular Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address: a.schinkel@nki.nl.
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D004347:Drug Interactions; D015870:Gene Expression; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D000077146:Irinotecan; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics* / Q000378:metabolism; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D027701:Organic Cation Transport Proteins / Q000172:deficiency / Q000235:genetics*; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D017671:Platinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D000077157:Sorafenib; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D002166:Camptothecin; D004317:Doxorubicin; D000077146:Irinotecan; D027381:Liver-Specific Organic Anion Transporter 1; D008727:Methotrexate; D009536:Niacinamide; D027701:Organic Cation Transport Proteins; D010671:Phenylurea Compounds; D017671:Platinum Compounds; D000077157:Sorafenib; D043823:Taxoids; C572127:SLCO1A1 protein, mouse; C503999:SLCO1B1 protein, human
keywords: Drug disposition; Drug–drug interactions; Hepatic uptake; OATP1A/1B transporters; OATP1B1; OATP1B3