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Vol. 26, Issue 3, 229-233, March 1998
Institut de Pharmacologie et de Biologie Structurale (B.M., I.R.,
P.A., S.C., M.W.),
Centre Claudius Regaud (E.C., A.D., H.R., P.C.), and
Institute de Chimie des Substances Naturelles, Centre National de la
Recherche Scientifique (J.D.)
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
6
-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 6
-hydroxycortisol/cortisol in urine, an index of
CYP3A activity. These findings emphasize the influence of pretreatment
with corticoids on the disposition of paclitaxel.
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