Effects of co-medicated drugs on cyclophosphamide bioactivation in human liver microsomes

The alkylating agent cyclophosphamide (CP) is a prodrug requiring cytochrome P-450-mediated bioactivation to form the active 4-hydroxycyclophosphamide (4OHCP). Modifications in the rate of CP bioactivation may have implications for the effectiveness of CP therapy, especially in high-dose regimens. In this study, agents frequently co-administered with CP in high-dose chemotherapy regimens were tested for their possible inhibition of the bioactivation of CP in human liver microsomes. The Km and Vmax values for the conversion of CP to 4OHCP were 93 microM and 4.3 nmol/h.mg, respectively. No inhibition was observed for aciclovir, carboplatin, ciprofloxacine, granisetron, mesna, metoclopramide, ranitidine, roxitromycin and temazepam. Inhibition was observed for amphotericin B, dexamethasone, fluconazole, itraconazole, lorazepam, ondansetron and thiotepa, with IC50 values of 50, >100, >50, 5, 15, >100 and 1.25 microM, respectively. For all but thiotepa, these IC50 values were higher than the therapeutic drug levels and thus considered of no clinical relevance. We conclude that of the tested co-medicated agents, only thiotepa inhibited metabolism of CP to 4OHCP at clinically relevant concentrations, and may thereby influence therapeutic and toxic responses of CP therapy.