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.

Imaging techniques to study drug transporter function in vivo

“…Direct murine orthologues do not exist for some drug transporters. For example, in the sinusoidal membrane of human hepatocytes the SLCO transporters OATP1B1, OATP1B3 and OATP2B1 are expressed, whereas in mouse hepatocytes mOATP1B2, mOATP2B1, mOATP1A1 and mOATP1A4 are expressed (Durmus et al, 2016).…”

“…mOATP1A1 and mOATP1A4 are mouse orthologues of human OATP1A2, which in the human liver is not expressed in the sinusoidal hepatocyte membrane but in epithelial cells of the bile duct. Owing to these differences, preclinical data on OATP-mediated transport in rodent liver is notoriously difficult to extrapolate to humans (Durmus et al, 2016) (Fig. 6).…”

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology

“…These humanized mice have allowed for better study of the effect of each human transporter individually. The limitations for the use of these mouse models were summarized in a recent review and should be considered when interpreting data from mouse model studies given the lack of direct rodent orthologs for important OATP transporters (Durmus et al, 2016). To date, no mouse model has been published for OATP2B1.…”

A novel fluorescence‐based functional assay for human OATP1A2 and OATP1C1 identifies interaction between third‐generation P‐gp inhibitors and OATP1A2

“…The major physiological substrates of OATPs are steroid and thyroid hormones, prostaglandins, bile acids, and bilirubin . However, several members of the OATP family, OATPs, 1A2, 1B1/1B3, and 2B1, are multispecific transporters that recognize a large variety of chemically diverse molecules, including not only endogenous substrates but also clinically applied drugs, for example, antivirals, chemotherapeutics, and statins . These polyspecific OATPs therefore influence drug absorption, distribution, and toxicity, and have been in the focus of extensive research .…”

“…Endogenous substrates of OATP1A2 include bile acids, bilirubin, steroid and thyroid hormones, prostaglandin E2, and all‐trans‐retinol . In addition, OATP1A2 mediates the cellular intake of numerous chemically unrelated compounds from antihistamines through statins to chemotherapeutic agents . OATP1A2 may also be the site of drug–drug or food–drug interactions .…”