Increased activity of CYP3A enzyme in primary cultures of rat hepatocytes treated with docetaxel: comparative evaluation with paclitaxel

Purpose: Docetaxel, a potent antimicrotubule agent widely used in the treat ment of ovarian, breast and lung cancer, is extensively metabolized in vari ous animal species, including humans. The metabolism of docetaxel to its pr imary metabolite, hydroxydocetaxel, is mediated by cytochrome P450 isozymes CYP3A2 and CYP3A4 in rats and humans, respectively. Several substrates of enzymes belonging to the CYP3A subfamily are known to induce different CYP isozymes, including CYP3A enzymes. Recently, paclitaxel, a compound structu rally related to docetaxel, has been shown to significantly elevate the exp ression of CYP3A in rat and human hepatocytes. In this study we investigate d the influence of docetaxel, employed at clinically relevant concentration s, on the level and the activity of cytochrome P450 3A in primary cultures of rat hepatocytes. Methods: Rat hepatocytes were treated with different co ncentrations of docetaxel, paclitaxel and other CYP3A inducers. Testosteron e 6 beta -hydroxylase activity of intact hepatocytes was used as a marker f or CYP3A. The immunoreactive CYP3A levels in the S-9 fractions were determi ned by Western blot analysis. Results: We observed that by day 3 of drug tr eatment, docetaxel at concentration in the range of 2.5-10 muM increased th e CYP3A enzymatic activity and the immunoreactive CYP3A levels in a concent ration-dependent manner. At the 10 muM level, docetaxel caused a twofold in crease in the CYP3A activity and a threefold increase in the immunoreactive CYP3A levels. However, the docetaxel-mediated CYP3A activity and enzyme le vel increase were significantly lower than those mediated by paclitaxel and dexamethasone. A comparison of the testosterone 6 beta -hydroxylation acti vity in hepatocytes treated with these agents at a concentration of 5 muM e ach yielded the following rank order of induction capacity: dexamethasone > paclitaxel > docetaxel (15-fold, 5-fold, 2.2-fold, respectively). Conclusi ons: Taken together, our findings raise the possibility that docetaxel at c linically relevant concentrations increases CYP3A activity. The potential f or docetaxel-mediated changes in the metabolism of other coadministered dru gs and its own metabolism, in relation to that due to paclitaxel, are discu ssed.