Modification of paclitaxel metabolism in a cancer patient by induction of cytochrome P450 3A4.
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 6alpha-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 6beta-hydroxycortisol/cortisol in urine, an index of CYP3A activity. These findings emphasize the influence of pretreatment with corticoids on the disposition of paclitaxel.
Monsarrat
B
B
Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Toulouse, France.
Chatelut
E
E
Royer
I
I
Alvinerie
P
P
Dubois
J
J
Dezeuse
A
A
Roche
H
H
Cros
S
S
Wright
M
M
Canal
P
P
D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001646:Bile / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008775:Methylprednisolone / Q000494:pharmacology; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000502:physiology*; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel; D008775:Methylprednisolone