Stephanie van Hoppe

136 Chapter 6 the liver uptake and plasma clearance of a range of compounds. Strong support for the functional activity of the hepatic OATP1B1, -1B3 and -1A2 transporters in the humanized strains came from the reversal of the highly increased plasma bilirubin levels found in the Oatp1a/1b(-/-) mice relative to wild-type mice (van de Steeg et al., 2013). The increased plasma levels of bilirubin monoglucuronide and diglucuronide were reversed to nearly wild-type levels (>15-fold and >7-fold reduction, respectively) by both OATP1B1 and OATP1B3 expression, whereas OATP1A2 caused a more modest 2-fold reduction. Interestingly, transgenic OATP1A2 was the only transporter that could significantly reduce the 2-fold increased levels of unconjugated bilirubinback towild-type levels.This suggests that OATP1A2 is a relativelymore efficient transporter of unconjugated bilirubin compared to conjugated bilirubin, whereas the inverse is true for OATP1B1 and OATP1B3. What this means for the normal biological function of human OATP1A2 in cholangiocytes is as yet unclear. Perhaps it plays a role in the resorption of highly insoluble unconjugated bilirubin inadvertently formed in bile, thus reducing the chance of formation of bilirubin-containing gallstones, but for the moment this possibility remains speculative. A limited pharmacokinetic study of paclitaxel in the OATP humanized mice revealed a modest, ~1.6-fold, but highly significant effect of OATP1B3 and OATP1A2 in enhancing the liver uptake of paclitaxel dosed i.v. at 2 mg/kg compared to that in Oatp1a/1b knockout mice. A smaller effect was observed at 10 mg/kg i.v. paclitaxel (only significant for OATP1A2). Transgenic OATP1B1 did not elicit significant changes relative to Oatp1a/1b(-/-) mice at either dose (van de Steeg et al., 2013). Collectively, these data suggest that OATP1B3 and perhaps OATP1B1 may only have modest effects on paclitaxel liver uptake and clearance in humans. It should be kept in mind, though, that, unlike the situation in single humanized mice, in human liver OATP1B1 and OATP1B3 usually function simultaneously, which could well enhance their overall pharmacokinetic impact by additive effects. Such an additive effectwas indeedobserved for another drug in recently generated OATP1B1/1B3 double-transgenic mice, where single OATP1B1 or OATP1B3 transgenes did not markedly reduce the AUC of pravastatin after i.v. administration, but the combination reversed the AUC to close to that seen in wild-type mice (Salphati et al., 2014). 2 . 1 . 2 . Do ce t a xe l Although quantitatively divergent results have been obtained for the impact of Oatp1b2 and Oatp1a/1b knockouts, and of various OATP1A2/1B1/1B3 humanized transgenes on docetaxel pharmacokinetics, all studies to date support a role of these OATP/Oatps in docetaxel clearance. De Graan et al. (2012) reported that after i.v. administration of docetaxel at 10 mg/kg to wild-type and Oatp1b2(-/-) mice, the plasma AUC was 26.3-