PHARMACOKINETICS AND METABOLISM OF SODIUM 2-MERCAPTOETHANESULFONATE IN THE RAT

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (1) , 333-338
Abstract
The synthetic low molecular weight thiol, 2-mercaptoethanesulfonate (mesna), exerts efficient protection against oxazaphosphorine-induced urothelial toxicity by binding the renally excreted and concentrated toxic metabolite(s). The pharmacokinetics and metabolism of mesna and its disulfide form (dimesna) were investigated in the intact rat and in several in vitro systems, including isolated perfused organs, freshly isolated cells and subcellular fractions; the mechanism of reduction of dimesna to form the pharmacologically active thiol mesna was further studied with purified enzyme preparations. After oral administration, mesna and dimesna are both absorbed from the intestine, and dimesna undergoes reduction to mesna during intestinal absorption. When present in plasma, mesna is rapidly oxidized to dimesna by a metal-dependent reaction. Mesna and dimesna pass unchanged through the hepatic vasculature, are not taken up into liver cells and are not excreted in bile. In the kidney, dimesna is filtered through the glomeruli and subsequently reabsorbed; reduction to the pharmacologically active thiol form occurs in the renal tubular epithelium, and the thiol is then reexcreted in the tubular lumen. Reduction of dimesna to mesna occurs in intestinal and renal epithelial cells by a mechanism involving the cytosolic enzymes thiol transferase and glutathione reductase. The formation of the pharmacologically active thiol form from dimesna is associated with the consumption of equimolar concentrations of reduced glutathione.