Stephanie van Hoppe

147 The impact of OATPs on disposition and toxicity of antitumor drugs; insights from KO and humanized mice background. Although this specific combination of drugs (methotrexate and rifampicin) would be rare in the clinic, these results still suggest that more than one OATP-substrate or -inhibitor drugs might bring the risk of drug-drug interactions at the systemic and hepatic level. This would be especially important for patients chronically taking OATP- interacting drugs, such as statins and hypertension drugs. More importantly, people who already have activity-reducing polymorphisms in their OATP genes (Nakanishi and Tamai, 2012) might be at increased risk for altered drug disposition due to this type of drug-drug interactions, and consequently ineffective treatment and/or increased toxicity. The possible drug-drug interaction effect of a clinically more common drug combinationwas investigatedusingahypertensivedrug, telmisartan, andmethotrexate. This also allowed further evaluation of the applicability of knock-out and humanized mouse strains in drug-drug interaction studies. A similar set-up to the rifampicin and methotrexate experiments was chosen, but the dose of telmisartan had to be kept lower (7 mg/kg) due to solubility issues. In vitro cellular uptake studies resulted in fairly but not very low IC 50 levels for telmisartan inhibiting methotrexate uptake (<11 µM), and in vivo studies in the mouse models showed that telmisartan pre-treatment did not yield important changes in methotrexate disposition. There was only a weak inhibition of OATP1B1-mediated hepatic uptake of methotrexate by telmisartan, leading to ~2-fold decreased liver-to-plasma ratios of methotrexate. However, comparing the systemic telmisartan levels (40 - 200 nM) in patients (Stangier et al., 2000) with the levels achieved in mouse plasma (7 - 13 µM) suggests only a very low risk of adverse OATP-mediated drug-drug interactions between telmisartan and methotrexate in the clinic. These findings are helpful for patients who are simultaneously treated with methotrexate and telmisartan. However, additional clinically relevant combinations of drugs that are OATP-substrates and/or -inhibitors should be tested to evaluate the risks of OATP-mediated drug-drug interactions in the clinic, especially for the systemic and hepatic effects on drug concentrations due to the function of OATPs in liver uptake of their substrates. We suggest that the humanized transgenic mouse models with liver- specific OATP expression could be used to obtain a more realistic view of the human situation. However, it should be noted that these mouse models, while very useful to support the development of basic mechanistic insights, should not be used as simple one-to-one models of drug behavior in humans. 2 . 4 . Doxo r ub i c i n Doxorubicin, an important topoisomerase II inhibitor drug used in cancer treatment, was recently shown to be an OATP substrate (Durmus et al., 2014). Doxorubicin is an