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Division of Hematology/Oncology [J. H., A. S., L. H. B.], General Clinical Research Center [P. B. W.], and Biostatistics Care [M. S.], University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109, and Rhône-Poulenc Rorer, Antony Cedex 92165, France [R. B.]
Docetaxel
is a chemotherapeutic agent effective in the treatment of various solid
tumors. Patients given a standard dose of docetaxel exhibit wide
interpatient variation in clearance (CL) and toxic effects. Docetaxel
undergoes metabolism by cytochrome CYP3A4. Thus, interpatient
variability in CYP3A4 activity may account in part for differences in
toxicity and CL. Twenty-one heavily pretreated patients with metastatic
sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4
activity in each patient was measured by the
[14C-N-methyl]erythromycin breath test
(ERMBT). Blood samples were taken at selected times over the next
24 h for pharmacokinetic analysis. Phenotypic expression of
hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold
(administered 14C exhaled in 1 h: mean, 2.53%; range,
0.25–5.35%), which is similar to a normal control population.
CL of docetaxel varied nearly 6-fold (mean, 21.0
liters/h/m2; range, 5.4–29.1 liters/h/m2). The
ERMBT was the best predictor of CL when compared with serum alanine
aminotransferase, albumin, alkaline phosphatase, or serum 
-1-acidic
glycoprotein. The natural log of ERMBT accounted for 67% of the
interpatient variation in CL. Multivariate analysis showed that the
natural log of ERMBT and albumin together accounted for 72% of the
interpatient variation in CL. The greatest toxicity was seen in
patients with the lowest ERMBT. Hepatic CYP3A4 activity is the
strongest predictor of docetaxel CL and accounts for the majority of
interpatient differences in CL. Patients with low CYP3A4 activity are
at risk for having decreased CL and may thus experience increased
toxicity from docetaxel. Those with high activity may be receiving a
suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be
clinically useful in tailoring doses of CYP3A4 substrates, such as
docetaxel, in certain individuals.
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