Modification of Paclitaxel Metabolism in a Cancer Patient by Induction of Cytochrome P450 3A4
- Bernard Monsarrat1,
- Etienne Chatelut2,
- Isabelle Royer1,
- Paul Alvinerie1,
- Joelle Dubois3,
- Annik Dezeuse2,
- Henri Roché2,
- Suzy Cros1,
- Michel Wright1 and
- Pierre Canal2
- 1Institut de Pharmacologie et de Biologie Structurale (B.M., I.R., P.A., S.C., M.W.), 2Centre Claudius Regaud (E.C., A.D., H.R., P.C.), and3Institute de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique (J.D.)
Abstract
Biliary, plasma, and urinary disposition of paclitaxel and paclitaxel metabolites were determined simultaneously in a patient with percutaneous biliary drain. The complete chemical structures of the major metabolites were established by mass spectrometry and NMR spectroscopy. A nonlinear elimination model was indicated by the fact that the rate of biliary excretion of paclitaxel rose as plasma concentrations fell. Dihydroxypaclitaxel was the predominant biliary metabolite, in contrast to the barely detectable levels in two previous patients. This derivative results from hydroxylation at the C6 position of the taxane ring and at the phenyl C3′-position on the C13 side chain mediated by cytochrome P450 2C8 and 3A4, respectively. In line with this mechanism, the two other main metabolites corresponded to 6α-hydroxypaclitaxel and to the paclitaxel derivative hydroxylated in the para-position on the phenyl ring at the C3′-position of the C13. A high CYP3A4 activity in the patient is consistent with the repeated administration of methylprednisolone for 14 days before paclitaxel treatment, a compound known to induce the CYP3A isoform, and with the increased ratio of 6β-hydroxycortisol/cortisol in urine, an index of CYP3A activity. These findings emphasize the influence of pretreatment with corticoids on the disposition of paclitaxel.
Footnotes
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Send reprint requests to: Dr. Monsarrat Bernard, Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, 205 route de Narbonne, 31077 Toulouse Cedex, France.
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This work was supported by a grant from l’Association pour la Recherche sur le Cancer and the Conseil Régional of Midi Pyrénées. Part of this research was presented previously at the 88th Annual Meeting of the American Association for Cancer Research in San Diego, CA.
- Abbreviations used are::
- CYP3A4 and CYP2C8
- cytochrome P450 isoform 3A4 and 2C8
- AUC
- area under the concentration-time curve
- HPLC
- high performance liquid chromatography
- LC/MS-APCI
- liquid chromatography/mass spectrometry-atmospheric pressure chemical ionization mode
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- Received June 16, 1997.
- Accepted November 25, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
