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 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 alpha-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.
Hirth
J
J
Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109, USA.
Watkins
P B
PB
Strawderman
M
M
Schott
A
A
Bruno
R
R
Baker
L H
LH
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism; D001944:Breath Tests; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000077143:Docetaxel; D004917:Erythromycin / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009961:Orosomucoid / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000378:metabolism; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; D009961:Orosomucoid; D043823:Taxoids; D000077143:Docetaxel; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000410:Alanine Transaminase; D017239:Paclitaxel