Correlation between docetaxel clearance and estimated cytochrome P450 activity by urinary metabolite of exogenous cortisol.

Abstract

There is no simple and practical method for the estimation of the interpatient variability of cytochrome P450 (CYP3A4) enzyme activity. Cortisol is metabolized by this enzyme and excreted as 6-beta-hydroxycortisol (6beta-OHF) and free-cortisol (FC) in urine, and docetaxel is also metabolized by hepatic CYP3A4 enzyme. We developed a new method for the estimation of CYP3A4 activity by measuring urinary cortisol metabolite after administration of exogenous cortisol. This study was aimed at assessing the predictability of the individual activity of CYP3A4 estimated by this method. Thirty patients with advanced non-small-cell lung cancer were entered onto this study. Hydrocortisone 300 mg was administered intravenously, and urinary 6beta-OHF and FC were measured. More than 2 days later, 60 mg/m(2) of docetaxel was administered intravenously with pharmacokinetic sampling. The correlation between docetaxel pharmacokinetics and estimated interpatient variability of CYP3A4 activity with the application of our method was assessed. After cortisol administration, the total amount of 24-hour urinary 6beta-OHF (T6beta-OHF) increased about 60-fold compared with pretreatment levels, averaging 12,273 +/- 4,076 microg/d (mean +/- SD). Docetaxel clearance (CL) and area under the concentration-time curve averaged 24.5 +/- 6.4 L/h/m(2) and 2.66 +/- 0.91 mg/L 8729. h, respectively. An excellent correlation between docetaxel CL and T6beta-OHF was observed (r =.867). In multivariate analysis, T6beta-OHF (P <.001), alpha-1-acid glycoprotein (P <.004), AST (P =.007), and age (P =. 022) significantly correlated with docetaxel CL. The interpatient variability of CYP3A4 activity and docetaxel CL could be predicted by measuring T6beta-OHF after cortisol administration.