Abstract
We have developed and validated an analytical methodology for the quantification of docetaxel and its four major human oxidation metabolites in mouse plasma. We have used this procedure to study the pharmacokinetics and metabolism of docetaxel in female FVB mice, receiving 2.5, 10, or 33 mg/kg of docetaxel by i.v. injection. We have also studied the pharmacokinetics of polysorbate 80, because it was shown previously that the vehicle substance Cremophor EL, which is used in the formulation of paclitaxel, exerts a profound effect on the pharmacokinetics of this compound. Linear pharmacokinetics of docetaxel was observed at dose levels between 2.5 and 10 mg/kg, where plasma levels corresponded to those in patients receiving the maximum tolerated dose. At the highest dose level of 33 mg/kg, a deviation from the linear kinetics was observed. Compared with humans, mice could tolerate much higher plasma levels, suggesting that the toxic side effects are related to a certain plasma threshold concentration instead of area under the curve or Cmax. At the highest dose level, three docetaxel metabolites could be detected in the plasma samples of mice for up to 4 h after drug administration. The hydroxy metabolite of the tert-butoxy group (metabolite II) was the major metabolite, followed by the two epimeric hydroxyoxazolone-type compounds (metabolites I and III). A fourth putative metabolite (e.g., the cyclic oxazolidinedione derivative) was not detected. Because of rapid degradation of polysorbate 80 by esterases in plasma, the concentration of this vehicle substance declined very rapidly. Consequently, this substance was not able to interfere in the disposition of docetaxel.