Differences in the induction of cytochrome P450 3A4 by taxane anticancer drugs, docetaxel and paclitaxel, assessed employing primary human hepatocytes.
OBJECTIVE
The induction of cytochrome P450 (CYP) 3A4 by drugs and other xenobiotics is a common cause of serious drug interactions. The aim of this study was to comparatively examine the effects of paclitaxel and docetaxel, two structurally related taxane anticancer agents, on the activity and expression of hepatic CYP3A4.


METHODS
Employing primary cultures of human hepatocytes from multiple donors, we investigated the differences in the magnitude of CYP3A4 induction and relative accumulation of paclitaxel and docetaxel. The CYP3A4 activity of intact hepatocytes was measured as the rate of testosterone 6beta-hydroxylation. The CYP3A4-specific immunoreactive protein and mRNA levels were measured employing Western blot and Northern blot analysis, respectively. Furthermore, employing cell-based reporter gene assay in CV-1 cells, we evaluated the capacity of paclitaxel and docetaxel to activate human pregnane X receptor (hPXR), an orphan nuclear receptor that plays a key role in the transcriptional regulation of CYP3A4.


RESULTS
In concurrence with previous reports, we observed that paclitaxel potently induced CYP3A4 activity and expression in hepatocytes treated for 48-96 h. However, docetaxel did not increase the activity or the CYP3A4 immunoreactive protein levels for treatment periods up to 96 h. A marginal increase in the CYP3A4 mRNA levels was observed in cells treated with higher levels (5 and 10 microM) of docetaxel. Furthermore, while paclitaxel effectively activated hPXR (the half-maximal effective concentration, EC50, being about 5.2 microM), docetaxel weakly activated hPXR, and moreover the activation occurred only at high concentrations relative to paclitaxel. A comparison of the cellular concentrations of paclitaxel and docetaxel, in the cell culture models employed for evaluating CYP3A4 induction and hPXR activation, revealed that the intracellular paclitaxel levels were three-fold higher than that of docetaxel. Thus, it appears that both pharmacokinetic (drug concentration) and pharmacodynamic differences (hPXR activation) may account for the observed differences in CYP3A induction by paclitaxel and docetaxel.


CONCLUSIONS
Our studies suggest that docetaxel has markedly reduced propensity to cause drug interactions that may entail hepatic CYP3A4 induction.
Nallani
Srikanth C
SC
College of Pharmacy, University of Cincinnati Medical Center, 3223 Eden Avenue, Cincinnati, OH 45267, USA.
Goodwin
Bryan
B
Buckley
Arthur R
AR
Buckley
Donna J
DJ
Desai
Pankaj B
PB
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects; D000077143:Docetaxel; D004347:Drug Interactions; D004790:Enzyme Induction; D022781:Hepatocytes / Q000473:pathology*; D008099:Liver / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology; D011987:Receptors, Steroid / Q000187:drug effects / Q000502:physiology; D043823:Taxoids / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel