Enhanced oral bioavailability of docetaxel by coadministration of cyclosporine: quantitation and role of P-glycoprotein.

Abstract

oral CL Doseoral where CL is the total clearance of drug in the body. A review of their article revealed that their calculation of the absolute bioavailability of docetaxel in the control study without cyclosporine was correctly determined because the CL was determined after intravenous admin- istration without cyclosporine. The authors used the same CL value to determine absolute bioavailability of docetaxel when cyclosporine was coadministered in the interaction study, apparently assuming no change in the CL of docetaxel by cyclosporine. However, such a critical assumption is inconsistent with reports that cyclosporine, a cytochrome P450 3A inhibitor, may also decrease CL for other cytochrome P450 3A substrates. For example, oral administration of cyclosporine 50 mg/kg has been reported to decrease the CL of intravenous paclitaxel by approximately 70% (from 0.92 0.07 to 0.28 0.01 L/h/kg) in mice. 4 Therefore, it seems likely that docetaxel's mean absolute bioavailability of 90% reported by Malingreet al in their interaction study may be considerably overestimated. This overestimation of oral bioavailability may also have occurred with their earlier study 5 on the effect of coadministration of oral cyclosporine on the absolute bioavail- ability of paclitaxel in patients, because the new CL during the interaction study was not obtained and only the same CL obtained during the control study was used to calculate absolute bioavailability. In that study, an eight-fold higher absolute bioavailability value of paclitaxel was reported because of cyclosporine coadministration. 5 Malingree t al 1 also found significant amounts of four metabolites of docetaxel in plasma after coadministration with cyclosporine. These metabolites, interestingly, were not detected in plasma after oral administration of the drug alone. They stated that such increased metabolism after coadministration with cyclosporine may result in lower levels of the active drug and, possibly, reduced efficacy. They further stated that the achieved gain in increased uptake largely outweighs the possible loss by the increased metabolism. 1 We wish to point out that increased metabolism per se may not necessarily result in lower levels of the parent drug, even if one assumes no change in uptake. In addition to oral bioavailability, plasma levels and AUC oral are determined by CL. The above-mentioned lower CL of docetaxel with coadministration of cyclosporine is theoretically expected to increase its plasma levels and AUCoral. In addition to the above- mentioned direct inhibition of the enzymatic activity by cyclosporine, P-glycoprotein may also play an important role in affecting the CL of docetaxel. For example, compared with wild-type mice, the CL of erythromycin 6-8 and paclitaxel 9 was markedly reduced and their plasma drug levels were markedly increased in P-glycoprotein knockout mice after intravenous administration, despite their higher metabolite levels (ie, increased metabolism) and their virtually identical hepatic enzyme contents. The decrease in the metabolic clearance of erythromycin and paclitaxel has been attributed mainly to the indirect inhibition of metabolism of parent drug due to accumulation of metabolites, also assumed to be P-glycoprotein substrates, in hepatocytes and entero- cytes. 7,8,10,11 For tacrolimus, which is metabolized almost exclusively in the body, hepatic metabolic clearance and apparent hepatic intrinsic clearance have been estimated to be reduced by 65% and 90%, respectively, in the P-glycoprotein knockout mice compared with wild-type mice, apparently due to the same mechanism. 10 It is possible that cyclosporine, a potent P-glycoprotein inhibitor, may also signifi- cantly decrease the hepatic and intestinal metabolic clearance of docetaxel by the same P-glycoprotein-mediated mechanism. It is hoped that the above discussions may be of interest to your readers and may stimulate further research in this rapidly evolving area.