Stephanie van Hoppe

152 Chapter 6 dependent on the cellular context in which they are expressed (in this case mouse hepatocytes). However that may be, for the moment it remains uncertain whether the observed clinical pharmacokinetic interaction between sorafenib and docetaxel is mediated through OATP1B1, or rather by some other mechanism(s). 3 . H e pato c y t e ho p p i ng o f a con j ug at e d an t i c an c e r drug : T h e c a s e o f s o r a f e n i b g lu c ur on i d e In contrast to the nearly absent effect of Oatp1b2 or Oatp1a/1b deficiency on the pharmacokinetics of orally administered sorafenib, in the same experiments a pronounced increase in plasma levels of sorafenib glucuronide was observed, with a 5.5-fold increased AUC in Oatp1b2(-/-) mice, and 29-fold in Oatp1a/1b(-/-) mice – although the bigger relative increase in the latter case mainly arose from a substantially lower AUC of sorafenib glucuronide in wild-type FVB mice than in wild-type DBA mice, with the plasma AUCs in both the knockout strains being similar (Zimmerman et al., 2013). The plasma levels of sorafenib glucuronide in the knockout strains equalled or surpassed those of parental sorafenib itself, indicating the quantitative importance of this process. Subsequent in vitro experiments indicated that sorafenib glucuronide was efficiently taken up by mouse Oatp1b2 and human OATP1B1 and OATP1B3 expressed in HEK293 cells. Furthermore, transgenic expression of either human OATP1B1 or OATP1B3 in the liver of “humanized” Oatp1a/1b(-/-) mice resulted in a partial reversal of the increased plasma sorafenib glucuronide levels (Zimmerman et al., 2013). This confirmed a prominent role of the mouse and human sinusoidal OATP proteins in hepatic uptake of sorafenib glucuronide. An important question was the origin of the sorafenib glucuronide, as it is known that both enterocytes and hepatocytes can have substantial drug glucuronidation capacity, and the oral sorafenib might have undergone rapid glucuronidation in the intestinal wall upon absorption. However, mouse intestinal microsomes showed only marginal sorafenib glucuronidation capacity, compared to mouse liver microsomes (>50-fold difference), suggesting that most sorafenib glucuronide had been formed in the liver (Zimmerman et al., 2013). Taken together, these findings suggested strongly that under normal conditions a substantial part of sorafenib glucuronide formed in the liver is extruded across the sinusoidal membrane into the blood, and then taken up again into the liver by Oatp1b2, OATP1B1, and OATP1B3.