URINARY-EXCRETION AND PHARMACOKINETICS OF ACROLEIN AND ITS PARENT DRUG CYCLOPHOSPHAMIDE IN BONE-MARROW TRANSPLANT PATIENTS

The urinary excretion and pharmacokinetics of acrolein (ACRO) and its parent drug cyclophosphamide (CP) were investigated in 16 randomly sel ected bone marrow transplant (BMT) recipients when CP was used for con ditioning. Patients suffering from aplastic anemia (n = 3) received a 4-day course of CP at a dose of 50 mg/kg daily infused intravenously ( i.v.) over Ih. Patients with leukemia (n = 13) were given either a com bination of busulphan followed by CP at a dose of 50 mg/kg infused i.v , over Ih for 4 days, or CP at a dose of 60 mg/kg by i.v. infusion ove r 1 h daily for 2 days followed by total body irradiation. Serial plas ma samples and urine were collected after the start of the first CP do se. CP was analyzed by capillary gas chromatography, whereas ACRO was measured in urine by liquid chromatography. The plasma concentration-t ime data for CP conformed to the two-compartment model and the mean an d s.e.m. values of alpha, beta, V-ss, total clearance, and renal clear ance observed were 1.29 (0.31) h(-1), 0.17 (0.03) h(-1), 0.67 (0.13) l /kg, 0.14 (0.02) I/h.kg, and 0.0188 (0.0052) l/h.kg, respectively. The mean and s.e.m. values of fraction of CP excreted in the form of ACRO during this interval (f(mu)) and ratio of the 24-h urinary concentrat ion of ACRO/creatinine (C-mu(n)) were 1.96 (0.35%) and 9.11 (2.19) mu g of ACRO/mg of creatinine, respectively. Two patients developed hemor rhagic cystitis (HC). Each of these two patients excreted significantl y (P < 0.01) more ACRO in the first and second 4-h urine collection pe riods. However, there was no significant difference in f(mu) or C-mu(n ) of ACRO between either of these two patients and the rest. This sugg ests that the rate of appearance of ACRO in urine is more crucial for developing HC than the cumulative amount excreted.