Stephanie van Hoppe

139 The impact of OATPs on disposition and toxicity of antitumor drugs; insights from KO and humanized mice by multidrug resistance caused by the MDR1 P-glycoprotein than docetaxel (Figg and Figg, 2010). Interestingly, cabazitaxel has a very similar structure as docetaxel, with the only difference being that two hydroxy groups in docetaxel are replaced by methoxy groups ( Figure 2 ). In spite of this great similarity to docetaxel, however, cabazitaxel appears not to be transported by human OATP1B1 and OATP1B3 or mouse Oatp1b2 in HEK293 cells, or in vivo in Oatp1b2 knockout mice (Nieuweboer et al., 2014). This illustrates how apparently minor structural modifications can sometimes have dramatic effects on whether a compound is transported by OATPs. On the plus side, this probably also means that for this drug, variations in OATP1B activity in patients due to genetic polymorphisms, drug-drug interactions or variable expression in tumors, are less likely to affect the therapeutic efficacy or toxicity. 2 . 2 . I r i no t e c an / SN - 38 The anticancer drug irinotecan is a topoisomerase I inhibitor widely used in the treatment of colorectal, ovarian and lung cancer. Its therapeutic index is quite low, in part owing to its complex pharmacokinetics involving a variety of metabolic enzymes and drug transporters. Irinotecan, essentially a prodrug, is hydrolyzed to its primary pharmacodynamically active metabolite, SN-38, by various carboxylesterases occurring in liver, intestine, and, in mice, also in plasma (Innocenti et al., 2009; Mathijssen et al., 2002). Severe toxic side effects of irinotecan therapy include diarrhea and neutropenia, and these generally correlate with the systemic exposure to SN-38 (Smith et al., 2006). Low-activity polymorphic variants of OATP1B1, which may lead to impaired hepatic clearance of irinotecan and/or SN-38, are associated with increased systemic exposure to SN-38 and life-threatening toxicity (Han et al., 2008; Takane et al., 2009; Xiang et al., 2006). It was therefore of great interest to improve our understanding of the in vivo impact of OATPs on irinotecan/SN-38 pharmacokinetics and toxicity using a panel of Oatp/OATP knockout and transgenic mice. As it turned out, however, this study also revealed a potentially important confounder in studies with these mouse strains for drugs that can be affected by plasma carboxylesterases. Initial studies of i.v. administered irinotecan (10 mg/kg) in wild-type and Oatp1a/1b(-/-)mice showed consistently higher plasma levels of irinotecan (AUC1.7-fold higher) and SN-38 (AUC 2.9-fold higher) in the knockout mice, and roughly similar liver concentrations, resulting in clearly decreased liver-to-plasma ratios of both compounds in the knockouts at virtually all time points (Iusuf et al., 2014). This is consistent with reduced uptake of both these compounds from blood into the liver in the absence of Oatp1a/1b transporters, causing higher plasma levels. The amount of plasma SN-38 as a fraction of plasma irinotecan was ~10% in wild-type mice, and ~23% in knockout mice. Amedium-term toxicity experiment, with daily i.v. administrations of irinotecan (30 mg/