Effects of paclitaxel, cyclophosphamide, ifosfamide, tamoxifen and cyclosporine on the metabolism of methoxymorpholinodoxorubicin in human liver microsomes.
The effects of paclitaxel, cyclosporine, cyclophosphamide, ifosfamide and tamoxifen on the metabolism of methoxymorpholinodoxorubicin (MMDx), a novel anticancer agent, were investigated using human liver microsomes. Paclitaxel, tamoxifen and cyclosporine dramatically inhibited MMDx metabolism, whereas ifosfamide had only a slight effect at high concentrations (200-300 microM) and cyclophosphamide had no effect. The inhibition was dependent on the concentrations of both MMDx and the coincubated drug. Thus, with 1 microM MMDx, paclitaxel (5 microM), tamoxifen (1 microM) and cyclosporine (1 microM) decreased the metabolic rate of MMDx by 36%, 53% and 62%, respectively. At higher concentrations (10, 5 and 5 microM, respectively, with paclitaxel, tamoxifen and cyclosporine) the inhibition was 52%, 91% and 91%, respectively. These three drugs preferentially inhibited the formation of three metabolites (M2, M3 and M6) among eight metabolites produced in liver microsomes. The inhibitory concentrations of paclitaxel, tamoxifen and cyclosporine on MMDx metabolism were in the range of those observed in patients upon administration of these drugs, which are known to be CYP3A4 substrates. These findings suggest that CYP3A4 drug substrates and MMDx in combination must be used with caution, particularly in view of the fact that MMDx is considered as a prodrug whose activation is entirely dependent upon metabolic transformation by CYP3A4.
Beulz-Riché
Dominique
D
Service de pharmacologie et Centre régional de pharmacovigilance, CHU de la Cavale Blanche, Bd Tanguy Prigent, 29609 Brest cedex, France.
Robert
Jacques
J
Riché
Christian
C
Ratanasavanh
Damrong
D
D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D003520:Cyclophosphamide / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007069:Ifosfamide / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D065607:Cytochrome P-450 Enzyme Inhibitors; D013629:Tamoxifen; C066998:methoxy-morpholinyl-doxorubicin; D004317:Doxorubicin; D016572:Cyclosporine; D003520:Cyclophosphamide; 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; D007069:Ifosfamide