Stephanie van Hoppe

134 Chapter 6 2 . R e c e n t pha rmaco lo g i c a l and to x i c i t y s t ud i e s w i t h OAT P kno c kou t and human i z e d m i c e 2 . 1 . Ta x ane s The taxanes paclitaxel and docetaxel are cytotoxic anticancer drugs that bind to microtubules and disrupt their function by stabilizing GDP-bound tubulin, thus interfering with proper cell division. Paclitaxel and docetaxel are currently applied intravenously (i.v.) in the treatment of several types of cancer, such as non-small cell lung cancer, ovarian, breast, gastric, prostate, and head-and-neck cancer (Gligorov and Lotz, 2004; Koolen et al., 2010). Both paclitaxel and docetaxel are quite large, very hydrophobic, uncharged molecules ( Figure 2 ). It was therefore thought that they could pass cell membranes primarily by passive diffusion, so it was initially a bit of a surprise that these molecules were substantially taken up into cells by OATP1B1 and OATP1B3 in several (but not all, see also section 4) in vitro expression systems (Baker et al., 2009; de Graan et al., 2012; Nieuweboer et al., 2014; Smith et al., 2006; Svoboda et al., 2011). To assess the possible in vivo relevance of this uptake transport, a number of studies with paclitaxel and docetaxel were performed in OATP/Oatp knockout and transgenic mice. 2 . 1 . 1 . Pa c l i t a xe l Van de Steeg et al. (2011) found that the paclitaxel plasma AUC was more than 2-fold increased in Oatp1a/1b(-/-) relative to wild-type mice after i.v. administration at 10 mg/kg. Conversely, the liver AUC was 2-fold lower in the Oatp1a/1b(-/-) mice. Clear differences in plasma and liver paclitaxel concentrations were not yet apparent at 3.5 minutes, but emerged from 7.5 minutes after administration. This suggests that the very early paclitaxel distribution, when plasma concentrations were very high (>20 mg/l), was not much dependent on Oatps. However, with plasma concentrations below 20 mg/l, paclitaxel liver uptake and hence plasma clearance became strongly dependent on Oatp1a/1b transporters. This suggested that at plasma levels above 20 mg/l the sinusoidal Oatp1a/1b proteins were saturated, and other uptake processes, perhaps passive diffusion, dominated the liver uptake of paclitaxel. This was supported by limited paclitaxel distribution studies at a higher dosage (50 mg/kg), which yielded reduced differences between Oatp1a/1b(-/-) and wild-type mice in plasma concentration (1.7-fold) and liver concentration (1.5-fold) 30 minutes after paclitaxel administration compared to the 10 mg/kg dose (1.9-fold and 2.2.-fold, respectively). Overall, the data indicate a substantial role of hepatic sinusoidal Oatp1a/1b proteins in the clearance of paclitaxel from plasma, at plasma concentrations that can also occur in patients. Following high-dose paclitaxel chemotherapy, peak plasma concentrations range from 2 to 11 mg/l (Rowinsky and Donehower, 1995), i.e. well below the saturation