SIMILAR BIOAVAILABILITY OF SINGLE-DOSE ORAL AND INTRAVENOUS MESNA IN THE BLOOD AND URINE OF HEALTHY-HUMAN SUBJECTS

Although mesna has been used for more than a decade to reduce the inci dence of hemorrhagic cystitis induced by ifosfamide and cyclophosphami de, the disposition of i,v, and oral mesna has not been adequately des cribed. To obtain accurate bioavailability data for the design of mesn a regimens, we developed procedures to preserve and measure mesna and dimesna in the blood and urine and studied 25 volunteer subjects who r eceived single doses of i,v, mesna and four different formulations of oral mesna in a five-way randomized crossover study. The dose-adjusted area under the blood concentration-time curve showed no difference in bioavailability for i,v, and oral mesna; however, the maximum mesna c oncentration after oral doses was 16% of that estimated for i,v, doses . The short initial half-life of i,v, mesna indicated that mesna was r apidly cleared; however, the blood concentrations of mesna uniformly e xceeded those of dimesna after oral as well as i,v, doses, which sugge sted that reduced mesna and oxidized mesna disulfide are in equilibriu m. The ratio of mesna:dimesna was higher in protein-free plasma than i t was in the urine, which suggested that most urinary mesna is produce d by glomerular filtration of mesna rather than by renal tubular reduc tion of dimesna, The sum of mesna and dimesna excretion after the i,v, doses (73% of the dose) and the four oral formulations (68-73%) showe d no difference in urinary bioavailability, consistent with the blood data. However, the urinary bioavailability of the therapeutically acti ve free-thiol mesna was greater after i,v, doses (40% of the dose) tha n it was after oral doses (31-33%), The ratio of oral:i,v, mesna excre tion ranged from 0.52-1.23 (mean, 0.82) among the 24 subjects. Urinary mesna concentrations exceeded 50 mu M in all subjects for up to 12 h after oral doses as compared to 4 h after i,v, doses. About 90% of thi s mesna was excreted by hour 2 after i,v, doses and by hour 9 after or al doses. The mean maximum concentration of mesna in blood and excreti on into urine were both 2.6 h after dosing. The oral formulations thus showed sustained urinary excretion, and their urinary bioavailability approached that of i,v, mesna.