Hepatic Uptake Transporters and Docetaxel Disposition in Mice

We previously reported in Clinical Cancer Research the results of a study evaluating the influence of hepatocellular OATP1B-type uptake transporters on the systemic clearance of docetaxel in mice and patients with inherited, reduced-function variants in the genes encoding these transporters (1). Figure 3A of this paper shows plasma levels of docetaxel in adult male DBA/1LacJ mice (wildtype), which served as control data for those obtained in Oatp1b2 knockout animals. At the time of our report, there were no reference values available for docetaxel pharmacokinetic parameters in this mouse strain and therefore we had no reason to a priori distrust the result. Upon further experimentation using what appear to be identical conditions, we recently found the plasma levels of docetaxel in wildtype DBA/1LacJ mice to be substantially higher than what we originally reported (2, 3).

While kinetic phenotypes of drugs often show considerable variability between different labs and/or within the same lab when experiments are performed over time, even in a genetically uniform mouse strain, the extent to which our original data differ from more recent findings (>10-fold) appears to be greater than what could have been expected from related literature on this topic. We have not been able to attribute these discrepancies to any particular reason (either biological, environmental, and/or analytical), and have not identified any calculation errors. Although the pharmacokinetic differences in question are of a quantitative nature and do not affect the posited conclusions of our original paper in a qualitative manner, based on the collective evidence now available, the original report likely overestimated the individual contribution of Oatp1b2 to the clearance of docetaxel in mice. This conclusion is consistent with recently reported data in the same mouse strain by another group (4), and is in better agreement with published studies on the related drug paclitaxel (5, 6).