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 K_m and V _max values for the conversion of CP to 4OHCP were 93 μM 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 μM, 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.