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Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients
Author(s) -
Ren Song,
Kalhorn Thomas F.,
McDonald George B.,
Anasetti Claudio,
Appelbaum Frederick R.,
Slattery John T.
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90178-3
Subject(s) - cyclophosphamide , pharmacokinetics , medicine , pharmacology , area under the curve , nitrogen mustard , chemotherapy
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 (CL f ) and elimination (CL m ) 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 CL f of 4‐hydroxycyclophosphamide increased 60% ( P < .001), its CL m 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. Clinical Pharmacology & Therapeutics (1998) 64 , 289–301; doi: