Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients.
OBJECTIVE
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.
Ren
S
S
Department of Pharmaceutics, University of Washington, Seattle, USA.
Kalhorn
T F
TF
McDonald
G B
GB
Anasetti
C
C
Appelbaum
F R
FR
Slattery
J T
JT
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D019540:Area Under Curve; D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013997:Time Factors
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D000444:Aldehyde Dehydrogenase