The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance

Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide int erpatient variation in clearance (CL) and toxic effects, Docetaxel undergoe s metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxcity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (1 00 mg/m(2)). Hepatic CYP3A4 activity in each patient was measured by the [C -14-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the nest 24 h for pharmacokinetic analysis, Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20- fold (administered C-14 exhaled in 1 h: mean, 2.53 %; range, 0.25-5.35%), w hich is similar to a normal control population. CL of docetaxel varied near ly 6-fold (mean, 21.0 liters/h/m(2); range, 5.4-29.1 liters/h/m(2)). The ER MBT was the best predictor of CL when compared,vith serum alanine aminotran sferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotei n. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albu min together accounted for 72% of the interpatient variation in CL, The gre atest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 a ctivity is the strongest predictor of docetaxel CL and accounts for the maj ority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxic ity from docetaxel. Those,vith high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in t ailoring doses of CYP3A4 substrates, such as docetaxel, in certain individu als.