Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients.

Autor: Ren S; Department of Pharmaceutics, University of Washington, Seattle, USA., Kalhorn TF, McDonald GB, Anasetti C, Appelbaum FR, Slattery JT
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 1998 Sep; Vol. 64 (3), pp. 289-301.
DOI: 10.1016/S0009-9236(98)90178-3
Abstrakt: Objectives: To characterize the pharmacokinetics of cyclophosphamide and 5 of its metabolites in bone marrow transplant patients and to identify the mechanism of the increase in 4-hydroxycyclophosphamide area under the plasma concentration-time curve (AUC) from day 1 to day 2 of cyclophosphamide administration.
Methods: Cyclophosphamide was administered by intravenous infusion (60 mg/kg over 1 hour, once a day) for 2 consecutive days to 18 patients. Cyclophosphamide and 4-hydroxycyclophosphamide concentration time data on day 1 and day 2 were fitted to a model to estimate 4-hydroxycyclophosphamide formation (CLf) and elimination (CLm) clearances. Erythrocyte aldehyde dehydrogenase-1 activity was measured ex vivo just before the first cyclophosphamide infusion was started (0 hours) and 24 hours after the second cyclophosphamide infusion (48 hours).
Results: From day 1 to day 2, the AUC of cyclophosphamide, deschloroethyl cyclophosphamide and phosphoramide mustard decreased 24.8%, 51%, and 29.4% (P < .02), the AUC of 4-hydroxycyclophosphamide 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 cyclophosphamide dose converted to 4-hydroxycyclophosphamide increased 16% (P < .001) from day 1 to day 2. The activity of patient erythrocyte aldehyde dehydrogenase-1 decreased 23.3% (P < .02) from 0 hours to 48 hours.
Conclusions: The AUC of 4-hydroxycyclophosphamide increased from day 1 to day 2 as a result of increased formation and decreased elimination clearances of 4-hydroxycyclophosphamide. Aldehyde dehydrogenase-1 activity appears to decline as a consequence of cyclophosphamide administration.
Databáze: MEDLINE
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