PHARMACOKINETICS OF CYCLOPHOSPHAMIDE AND ITS METABOLITES IN BONE-MARROW TRANSPLANTATION PATIENTS

Objectives: To characterize the pharmacokinetics of cyclophosphamide a nd 5 of its metabolites in bone marrow transplant patients and to iden tify the mechanism of the increase in 4-hydroxycyclophosphamide area u nder the plasma concentration-time curve (AUC) from day 1 to day 2 of cyclophosphamide administration.Methods: Cyclophosphamide was administ ered by intravenous infusion (60 mg/kg over I hour, once a day) for 2 consecutive days to 18 patients. Cyclophosphamide and 4-hydroxycycloph osphamide concentration-time data on day 1 and day 2 were fitted to a model to estimate 4-hydroxycyclophosphamide formation (CLf) and elimin ation (CLm) clearances. Erythrocyte aldehyde dehydrogenase-l activity was measured ex vivo just before the first cyclophosphamide infusion w as started (0 hours) and 24 hours after the second cyclophosphamide in fusion (48 hours),Results: From day 1 to day 2, the AUC of cyclophosph amide, deschloroethyl cyclophosphamide and phosphoramide mustard decre ased 24.8%, 51%, and 29.4% (P < .02), the AUC of 4-hydroxycyclophospha mide and carboxyethylphosphoramide mustard increased 54.7% and 25% (P < .01), whereas the AUC of phosphoramide mustard was not significantly changed (P > .3), The CLf of 4-hydroxycyclophosphamide increased 60% (P < .001), its CLm decreased 27.7% (P < .001), and the fraction of cy clophosphamide dose converted to 4-hydroxycyclophosphamide increased 1 6% (P < .001) from day 1 to day 2, The activity of patient erythrocyte aldehyde dehydrogenase-l decreased 23.3% (P < .02) from 0 hours to 48 hours. Conclusions: The AUC of 4-hydroxycyclophosphamide increased fr om day 1 to day 2 as a result of increased formation and decreased eli mination clearances of 4-hydroxycyclophosphamide. Aldehyde dehydrogena se-1 activity appears to decline as a consequence of cyclophosphamide administration.