Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients.
OBJECTIVE
The pharmacokinetics of cyclophosphamide (CY) and 4-hydroxycyclophosphamide (HCY) were studied in 14 patients being prepared for bone marrow transplantation with either busulfan (BU)/CY (n = 7) or CY/total-body irradiation (TBI) (n = 7) to determine whether exposure to CY and its proximate toxic metabolite HCY is modulated by other agents used in the preparative regimen.


METHODS
HCY was assayed by a new method that stabilized the metabolite at bedside. In BU/CY patients (who also received phenytoin), CY clearance was 112% greater (P = .0014), half-life 54% less (P = .0027), peak HCY concentration in plasma/CY dose 113% greater (P = .0006), and the ratio of area under the plasma concentration-time curves (AUCs) of HCY to CY 166% greater (P = .0116) than in CY/TBI patients. The ratio of the AUC of HCY/CY dose was 48% greater in BU/CY patients than in CY/TBI patients when one CY/TBI patient with an apparent impaired ability to eliminate HCY was excluded from analysis. In CY/TBI patients, there was an inverse correlation between the AUC of HCY and that of CY (R2 = .740, P = .028). Also, the ratio of the AUC of HCY/CY dose was correlated with the average concentration of BU at steady-state (Css, Bu) (R2 = .646, P = 0.29). Variability in CY and HCY pharmacokinetics among the 14 patients overall was pronounced, with the highest variability (15-fold) observed in the ratio of the AUC of HCY to that of CY.


CONCLUSIONS
Prior administration of BU and/or phenytoin significantly alters exposure to CY and HCY. Interpatient variability in HCY exposure at a given CY dose is substantial.
Slattery
J T
JT
Department of Pharmaceutics, University of Washington, Seattle, USA.
Kalhorn
T F
TF
McDonald
G B
GB
Lambert
K
K
Buckner
C D
CD
Bensinger
W I
WI
Anasetti
C
C
Appelbaum
F R
FR
D000328:Adult; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy*; D002066:Busulfan / Q000494:pharmacology; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007938:Leukemia / Q000378:metabolism / Q000628:therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged
C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D002066:Busulfan