Stephanie van Hoppe

126 Chapter 6 A B S T R AC T It is now widely accepted that organic anion-transporting polypeptides (OATPs) can have a strong impact on the disposition and elimination of a variety of endogenous molecules and drugs, especially members of the OATP1A/1B family. 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 many, structurally diverse anti-cancer and other drugs. Here, we present a critical assessment of the currently available OATP1A and OATP1B knockout and transgenic mouse models as tools to study in vivo OATP functions. 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 forbothendogenous andexogenous substrates. Interestingly, glucuronideconjugatesof both the heme breakdown product bilirubin and the 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 helped in a better mechanistic understanding of their functional relevance in drug pharmacokinetics, and their implications for therapeutic efficacy and toxic side effects of anticancer and other drug treatment.