Human liver microsomal metabolism of paclitaxel and drug interactions.

Article Details

Citation

Desai PB, Duan JZ, Zhu YW, Kouzi S

Human liver microsomal metabolism of paclitaxel and drug interactions.

Eur J Drug Metab Pharmacokinet. 1998 Jul-Sep;23(3):417-24.

PubMed ID
9842986 [ View in PubMed
]
Abstract

The aim of this study was to investigate the influence of several anticancer drugs and investigational multidrug resistance (MDR) reversing agents on the hepatic metabolism of paclitaxel (Taxol) to its primary metabolites, 6alpha-hydroxypaclitaxel (metabolite, MA) and 3'-p-hydroxypaclitaxel (metabolite, MB). There is significant inter-individual variability associated with the levels of these two metabolites. In many cases, 6alpha-hydroxypaclitaxel has been observed to be the predominant metabolite, in others, 3'-p-hydroxypaclitaxel has been the principal metabolite. The formation of 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel is catalyzed by cytochrome P450 isozymes CYP2C8 and CYP3A4, respectively. A number of factors, including co-administration of drugs and adjuvants, are known to influence the activity of these isozymes. Therefore, the influence of MDR reversing agents, R-verapamil, cyclosporin A (CsA) and tamoxifen and anti-cancer drugs doxorubicin, etoposide (VP-16) and cisplatin on paclitaxel metabolism was assessed employing human liver microsomes in vitro. Paclitaxel (10 microM) was incubated with human liver microsomes (1 mg protein, -0.34 nmol CYP) in the presence of a NADPH generating system at 37 degrees C for 1 h, with and without the presence of interacting drug. Controls included incubations with quercetin and ketoconazole, known inhibitors of 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel formation, respectively. At the end of the incubation period, paclitaxel and the metabolites were extracted in ethyl acetate and analyzed employing an HPLC method. Significant inhibition of paclitaxel conversion to 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel was observed in the presence of R-verapamil, tamoxifen and VP-16 (P 0.005). Doxorubicin significantly inhibited the formation of 3'-p-hydroxypaclitaxel and CsA inhibited the formation of 6alpha-hydroxypaclitaxel (P 0.005). This study demonstrates that co-administration of several of the above listed compounds could lead to significant changes in the pharmacokinetics of paclitaxel.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
PaclitaxelCytochrome P450 2C8ProteinHumans
Unknown
Substrate
Details
PaclitaxelCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
Drug Interactions
DrugsInteraction
Acenocoumarol
Etoposide
The therapeutic efficacy of Acenocoumarol can be increased when used in combination with Etoposide.
Dicoumarol
Etoposide
The therapeutic efficacy of Dicoumarol can be increased when used in combination with Etoposide.
Fluindione
Etoposide
The therapeutic efficacy of Fluindione can be increased when used in combination with Etoposide.
Phenindione
Etoposide
The therapeutic efficacy of Phenindione can be increased when used in combination with Etoposide.
Phenprocoumon
Etoposide
The therapeutic efficacy of Phenprocoumon can be increased when used in combination with Etoposide.