PHARMACOKINETICS OF MESNA AND DIMESNA AFTER SIMULTANEOUS INTRAVENOUS BOLUS AND INFUSION ADMINISTRATION IN PATIENTS UNDERGOING BONE-MARROW TRANSPLANTATION

This study was undertaken to examine the pharmacokinetics of mesna and its dimer form, dimesna, in the plasma and urine of patients undergoi ng bone marrow transplantation who received 130 mg/kg of mesna divided intravenously into a 30-mg/kg bolus dose followed immediately by 100 mg/kg infused over 12 hours for uroprotection. The relationship betwee n and urinary excretion of mesna and dimesna also was examined by comp aring the data obtained in patients tr ho developed hemorrhagic cystit is versus those who did not. Blood and urine samples were collected at different time intervals after administration, and the plasma or urin e was analyzed by liquid chromatography with electrochemical detection . Dimesna was analyzed in these samples after reduction back to mesna with sodium borohydride. The concentration-time data of mesna exhibite d the characteristics of the two-compartment model well, and the mean +/- SD values of the distributive phase half-life (t(1/2 alpha)), post distributive phase half-life (t(1/2 beta)), volume of distribution of the central compartment (Vd(c)), volume of distribution at steady stat e (Vd(ss)), volume of distribution during the postdistributive phase ( Vd,), total clearance (Cl), and mean residence time (MRT) observed wer e 0.12 +/- 0.15 hours, 2.12 +/- 3.61 hours, 0.324 +/- 0.336 L/kg, 1.09 +/- 1.18 L/kg, 2.09 +/- 3.0 L/kg, 0.755 +/- 0.507 L/hr.kg, and 6.77 /- 0.72 hours, respectively. The mean +/- SD values of t(1/2) and MRT of dimesna were 1.29 +/- 0.6 hours and 6.68 +/- 1.05 hours, respective ly, and the ratio of the area under the concentration-time curve (AUC) of mesna to that of dimesna was 1.21 +/- 0.57. The fractions of dose excreted in urine in the form of mesna and dimesna in 20 hours (f(u)) were 0.361 +/- 0.35 and 0.282 +/- 0.25, and the renal clearance (Cl-R) values were 0.244 +/- 0.201 L/hr.kg and 0.157 +/- 0.156 L/hr.kg, resp ectively. The urinary excretion of mesna in these patients was higher than that required for uroprotection for the whole duration of infusio n, and there was no significant difference in the pharmacokinetics of mesna between patients who developed hemorrhagic cystitis and those wh o did not. This was not the case with dimesna, in which patients with hemorrhagic cystitis excreted in urine less than 50% of the amount of dimesna excreted by those without hemorrhagic cystitis.