Depletion of circulating cyst(e)ine by oral and intravenous mesna

Abstract

Summary The sulfhydryl status of normal and tumour cells is critically important in determining their susceptibility to various cytostatic agents. As a sulfhydryl compound, mesna (sodium 2-mercaptoethanesulfonate) which is used in large doses to prevent haemorrhagic cystitis associated with certain chemotherapeutic regimens might derange cellular thiol homeostasis. In order to investigate the effects of mesna on the concentrations of thiols in plasma, cysteine, glutathione and their disulfides were measured by HPLC following the oral and intravenous administration of mesna to healthy volunteers. After 7.3 mmol mesna i.v. free cysteine rose from 8.2 (95% CI 7.0-9.4) nmol ml' to 53.6 (47.4-59.8) nmol ml-' at 5 min, most likely due to reduction of circulating cystine by the sulfhydryl drug. This initial rise was followed by a marked decrease of total cyst(e)ine in plasma from 276 (215-337) nmol ml-' to a nadir of 102 (McGown & Fox, 1986). Similarly, the sulfhydryl status of normal cells is an important determinant of their defense against the toxic effects of the same cytostatic drugs (Chasseaud, 1979). Mesna (sodium 2-mercaptoethanesulfonate) is increasingly used to prevent haemorrhagic cystitis associated with chemotherapeutic regimens containing high doses of ifosfamide and cyclophosphamide (Dechant et al., 1991). Although mesna is very polar and does not passively enter cells to a significant extent (Ormstad et al., 1983), the sulfhydryl drug could still markedly affect cellular thiol homeostasis. High concentrations of the sulfhydryl could reduce circulating cystine, thereby making more cysteine available to cells since cysteine is more readily taken up by many cell types than cystine (Issels et al., 1988). In addition, cysteine-mesna mixed disulfides have been identified in urine (Jones et al., 1985;Duran et al., 1981). Mesna might thus result in a substantial loss of cyst(e)ine. Since the effects of intravenous and oral mesna on circulating physiological thiols are not known and the mesna-induced loss of cyst(e)ine has not been quantitated, the concentrations of cysteine, glutathione and their disulfides in plasma and urine were measured following the oral and intravenous administration of mesna to healthy volunteers. Subjects and methodsThe effects of mesna (sodium-2-mercaptoethane-sulfonate) on plasma cyst(e)ine and glutathione after intravenous and oral administration were studied in eight healthy volunteers, two females and six men, 24 to 39 years of age, all within 10% of ideal body weight. Informed consent was obtained from each of the participants. The study was approved by the ethics committee of the local medical school. After an overnight fast an indwelling catheter was placed into an antecubital vein of both arms in order to obtain blood repeatedly without tourniquet. Two blood samples were obtained 10 min apart before the administration of mesna in order to determine the basal concentrations of glutathione and cyst(e)ine.Intravenous mesna was infused over 2 min at a dose of 1.2 g (7.3 mmol; AS...

Reperfusion Injury of the Liver: Role of Mitochondria and Protection by Glutathione Ester

“…Total and oxidized glutathione concentrations in mitochondria were determined by a spectrophotometer using the methods of Tietze [25] and Griffith [26], respectively. Sulfhydrils (cysteine, GSH, GSHE) in plasma and liver were measured by HPLC following derivatization of SH groups with monobromobimane [27,28]. ALT in plasma was assessed using an automated procedure.…”

Ifosfamide Clinical Pharmacokinetics

“…As with dimesna, these disulphides can be reduced to mesna and cysteine, which are then excreted into the urine (Jones et al 1985;StoferVogel et al 1993b;Wright et al 1985). Cysteine is able to react with ifosfamide metabolites in the same manner as mesna and, thus, cysteine is also 451 involved in regional detoxification (Shaw 1987;Stofer-Vogel et al 1993b).…”

“…However, its influence on renal tubular toxicity, which is only observed after administration of multiple highdoses of ifosfamide, remains unclear (Goren et al 1989;Stofer-Vogel et al 1993b). No data from clinical studies comparing administration of ifosfamide with and without mesna are available.…”

Mesna for Treatment of Hyperhomocysteinemia in Hemodialysis Patients

“…Several studies have demonstrated that mesna depletes plasma thiols such as cysteine and tHcy in patients who undergo chemotherapy. Stofer-Vogel et al (46) were the first to report that oral and intravenous mesna deplete the thiol amino acid cysteine by enhancing its urinary excretion. Similarly, Lauterburg et al (33) and Pendyala et al (34) showed depletion of tHcy by intravenous infusion of mesna to patients who were undergoing concurrent chemotherapy with ifosfamide.…”