RT Journal Article
SR Electronic
T1 Nonlinear Pharmacokinetics of Cyclophosphamide and 4-Hydroxycyclophosphamide/Aldophosphamide in Patients with Metastatic Breast Cancer Receiving High-dose Chemotherapy Followed by Autologous Bone Marrow Transplantation
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 544
OP 551
VO 25
IS 5
A1 Chen, Tian-Ling
A1 Kennedy, M. John
A1 Anderson, Lawrence W.
A1 Kiraly, Susan B.
A1 Black, Kraig C.
A1 Colvin, O. Michael
A1 Grochow, Louise B.
YR 1997
UL http://dmd.aspetjournals.org/content/25/5/544.abstract
AB The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide has been evaluated in 12 patients with metastatic breast cancer undergoing high-dose chemotherapy followed by bone marrow transplantation. Each patient received an initial dose of 4 g/m2 of cyclophosphamide over 90 min to prime peripheral blood progenitor cells (the first course), and 3 weeks later, 6 g/m2of cyclophosphamide with 800 mg/m2 of thiotepa by 96-hr infusion before marrow stem cell infusion (the second course). Whole blood cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide concentrations were measured by a GC-EIMS method using deuterium labeled compounds as internal standards. In addition, plasma and urine cyclophosphamide concentrations were determined by a GC assay. Whole blood concentrations of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide vs. time data and urinary excretion of cyclophosphamide data from the first course were co-modeled using a one-compartment model with Michaelis-Menten saturable elimination in parallel with first-order renal elimination (N = 7) or first-order metabolic and renal elimination (N = 5) for cyclophosphamide and one-compartment model with first-order elimination for 4-hydroxycyclophosphamide/aldophosphamide. The parallelism between cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide disposition curves implies that the pharmacokinetics of 4-hydroxycyclophosphamide/aldophosphamide is formation limited; only the fractional 4-hydroxycyclophosphamide/aldophosphamide clearance rate (Clmet/Fmet) can be estimated. The mean Vmax andKm for cyclophosphamide were 0.78 μM/min and 247 μM, respectively. The mean nonrenal clearance (Clnr) of cyclophosphamide for five patients with apparent first-order elimination of cyclophosphamide was 67 ml/min. The mean Clmet/Fmet of 4-hydroxycyclophosphamide/aldophosphamide was 2982 ml/min. The mean renal clearance (Clr) of cyclophosphamide was 29 ml/min and 24 ml/min for the first course and the second course, respectively. The correlations between cyclophosphamide AUCs and 4-hydroxycyclophosphamide/aldophosphamide AUCs were sought for both drug courses. Blood and plasma cyclophosphamide concentrations were remarkably similar, indicating that cyclophosphamide partitions equally in the red cell and plasma volume. Computer simulation of the effect of potential alterations in Michaelis-Menten saturable elimination and renal clearance on 4-hydroxycyclophosphamide/aldophosphamide has been used to illustrate the complex relationship between the exposure to parent compound and active metabolite. The American Society for Pharmacology and Experimental Therapeutics