Stephanie van Hoppe

137 The impact of OATPs on disposition and toxicity of antitumor drugs; insights from KO and humanized mice fold higher in Oatp1b2(-/-) mice, indicating a very large effect of Oatp1b2 removal. As expected, the liver-to-plasma AUC ratio was reduced in Oatp1b2(-/-) mice, by 6.2-fold. However, somewhat surprisingly, the liver docetaxel AUC itself was substantially higher (4.3-fold) in Oatp1b2(-/-) compared to wild-type mice, rather than lower (or perhaps equal, see below). This result was unexpected in case the liver uptake of docetaxel was strongly reduced in the knockout mice. An analysis of potential compensatory expression changes of functionally related genes in the knockout mice did not yield obvious alternative causes of the changes in docetaxel pharmacokinetics. A simple mechanistic explanation of the observed increased liver AUC of docetaxel in the Oatp1b2(-/-) mice is for the moment therefore still lacking. The potential experimental variability of these docetaxel pharmacokinetic studies was illustrated by the outcome of very similar experiments that were performed a few years later by the same group, in the same mouse strains, under apparently the same conditions (Hu et al., 2014; Sparreboom and Mathijssen, 2014). Instead of a 26- fold higher plasma AUC of docetaxel in the Oatp1b2(-/-) mice, only a 1.6-fold increase was observed, which was, however, still statistically significant. The main difference was not a change over time in the plasma AUC of the Oatp1b2(-/-) mice (~7400 vs. ~8800 ng x h/ml), but almost entirely attributable to a much higher plasma AUC of docetaxel in the wild-type mice compared to the earlier experiments (4500 vs. 336 ng x h/ml). Despite extensive later analyses by the same group, the cause of these divergent results is still unclear (Sparreboom and Mathijssen, 2014). Although in our experience it is not uncommon to see some variation in absolute drug levels (AUC) measured in pharmacokinetic studies performed a few years apart under otherwise seemingly identical conditions, this usually concerns less than about 2-fold differences. However this may be, collectively, the data still indicate a role for Oatp1b2 in the clearance of i.v. docetaxel, most likely by mediating uptake of docetaxel from blood into the liver. This was further corroborated by independent studies by two other groups. Using the same strain of Oatp1b2(-/-) mice, Lee et al. (2015) very recently reported a limited, 30 min pharmacokinetic study with i.v. [ 3 H]-docetaxel dosed at 1 mg/kg. Measuring plasma and liver radioactivity, they found a 5.5-fold higher plasma AUC of [ 3 H]-docetaxel equivalents in Oatp1b2(-/-) mice (340 +/- 149 vs 62 +/- 8 ng x h/ml, P < 0.05)), no significant difference in liver concentrations, but a 3-fold decreased liver- to-plasma ratio (P < 0.05). While concerning total radioactivity measurements, which may be complicated by extensive and possibly differential docetaxel metabolism, these results qualitatively support the findings of Hu et al. (2014) and De Graan et al. (2012), indicating a role of Oatp1b2 in plasma clearance of docetaxel by mediating uptake into the liver. Iusuf et al. (2015) studied docetaxel pharmacokinetics in Oatp1a/1b(-/-) mice of an