Urinary excretion and pharmacokinetics of acrolein and its parent drug cyclophosphamide in bone marrow transplant patients

Abstract

The urinary excretion and pharmacokinetics of acrolein (ACRO) and its parent drug cyclophosphamide (CP) were investigated in 16 randomly selected bone marrow transplant (BMT) recipients when CP was used for conditioning. 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 1 h. Patients with leukemia (n = 13) were given either a combination of busulphan followed by CP at a dose of 50 mg/kg infused i.v. over 1 h for 4 days, or CP at a dose of 60 mg/kg by i.v. infusion over 1 h daily for 2 days followed by total body irradiation. Serial plasma samples and urine were collected after the start of the first CP dose. CP was analyzed by capillary gas chromatography, whereas ACRO was measured in urine by liquid chromatography. The plasma concentration-time data for CP conformed to the two-compartment model and the mean and s.e.m. values of α, β, V_ss, total clearance, and renal clearance observed were 1.29 (0.31) h⁻¹, 0.17 (0.03) h⁻¹, 0.67 (0.13) l/kg, 0.14 (0.02) l/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 concentration of ACRO/creatinine (C_mu(n)) were 1.96 (0.35%) and 9.11 (2.19) μg of ACRO/mg of creatinine, respectively. Two patients developed hemorrhagic cystitis (HC). Each of these two patients excreted significantly (P < 0.01) more acro in the first and second 4-h urine collection periods. 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 suggests that the rate of appearance of ACRO in urine is more crucial for developing HC than the cumulative amount excreted.