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Sodium 2-mercaptoethane sulfonate (MESNA) is a thiol-containing compound that has proven to be effective in inactivating acrolein, the toxic metabolite of some anti-cancer drugs (e.g., cyclophosphamide and ifosphamide). Also, it scavenges free radicals which cause numerous disorders by attacking biological molecules. Current methods available to analyze MESNA in biological matrices include colorimetry and high-performance liquid chromatography (HPLC) with ultraviolet, fluorescence, or electrochemical detection. These methods have several limitations including low sensitivity, poor selectivity, a high degree of difficulty, and long analysis times. Hence, a rapid, simple, and sensitive HPLC tandem mass spectrometry (MS/MS) method was developed and validated to quantify MESNA in rat plasma following IP administration. The analysis of MESNA was accomplished via plasma protein precipitation, centrifugation, supernatant evaporation, reconstitution, and HPLC-MS/MS analysis. The method showcases an outstanding limit of detection (20 nM), excellent linearity (R 2  = 0.999, and percent residual accuracy >90%) and a wide linear range (0.05-200 μM). The method also produced good accuracy and precision (100 ± 10% and <10% relative standard deviation, respectively). The validated method was successfully used to analyze MESNA from treated animals and will allow easier development of MESNA for therapeutic purposes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sensitive electrophoretic method for determination of total sodium 2-mercaptoethanesulfonate (mesna) in human plasma, based on the stacking with high salt concentration in MEKC and in-capillary derivatization with 2-chloro-1-methyllepidinium tetrafluoroborate followed by UV detection was developed. In the method 0.03molL(-1)pH 7 phosphate buffer with the addition of 0.01molL(-1) SDS, and 10% ACN was used as a BGE. The limit of quantification (LOQ) of the method was 0.5μmolL(-1). Linearity in detector response was observed over the range of 0.5-10μmolL(-1) with the correlation coefficient 0.9971. The intra- and inter-day accuracy (three concentration levels, 5 days, n=3) of the method ranged from 97.2 to 110.0% and from 94.0 to 101.2%, respectively. The novel MEKC method with UV detection proved to be suitable for determination of total mesna in human plasma., (Copyright © 2016 Elsevier B.V. All rights reserved.)

BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate; Tavocept) is a novel water-soluble investigational agent that is undergoing clinical development for prevention and mitigation of cisplatin-induced nephrotoxicity. BNP7787 is a disulfide that undergoes thiol-disulfide exchange reactions in vivo with physiological thiols. Mesna-disulfide heteroconjugates that form as a result of these exchange reactions may play a key role in the protection against cisplatin-induced nephrotoxicity. Although several analytical methods have been used to detect thiols and disulfides, they have notable limitations including (i) low sensitivity, (ii) interference by chemical modification by derivatization reagents, and (iii) cumbersome sample preparation. In this paper, a sensitive micro-HPLC-EC method is described that identifies BNP7787 and mesna in plasma and phosphate buffer across a broad concentration range from 500nM to 100microM. This method utilizes a dual electrochemical detector equipped with a wall-jet gold electrode. The approach described here facilitates the identification of BNP7787 and mesna down to nanomolar levels. Although we did not focus on optimizing the approach for other thiol and disulfide compounds, we believe this approach could be optimized and used in the identification of other thiols and disulfides in plasma. The assay requires significantly less sample preparation and does not involve the use of derivatizing agents (i.e., the thiol and disulfide species can be detected directly) and represents an important advance over previous methods. This method was used to detect and quantitate BNP7787 and to monitor and kinetically characterize the interactions of BNP7787 with glutathione, cysteine, cysteinyl-glycine, cysteinyl-glutamate and homocysteine.

MESNA is the sodium salt of 2-mercaptoethane sulfonate, a thiol-containing drug. It is an antioxidant used particularly in renal protection. Several studies have proved that MESNA has beneficial effects in ischemic acute renal failure where it scavenges reactive oxygen species (ROS), due to the presence of the thiol group. It also reduces the size of urinary bladder cancer. MESNA was proved to be effective in preventing hemorrhagic cystitis induced by high doses of several chemotherapeutic regimens such as cyclophosphamide and ifosfamide. It has been shown that MESNA functions as an uroprotective substance in drug-induced experimental bladder cancer models. Moreover, recent studies have suggested that it is also effective in reducing intestinal inflammation in colitis. Because of the increased level of interest in using MESNA for treating various disorders, a new and sensitive method was needed to understand the pharmacokinetics of this drug. Accordingly, we developed a new method for determining free MESNA in biological samples by using ThioGlo-3 [3H-Naphto [2,1-b] pyran, 9-acetoxy-2-(4-(2,5-dihydro-2, 5-dioxo-1H-pyrrol-1-yl) phenyl-3-oxo)] as the derivatizing agent. MESNA was detected fluorimetrically by reverse-phase HPLC using acetonitrile:water (75:25) along with acetic acid and phosphoric acid (1 mL/L each) as the mobile phase. The detection limit was 1.64 nm per 20 microL injection volume, with a linearity (r = 0.999) in the calibration curve extending over a range 2.5-2500 nm. The coefficients of variation for within-run and between-run precision were 0.43 and 3.31%, respectively. The relative recoveries in the biological samples were in the range 87 +/- 6 to 93 +/- 2.4%. The concentrations of MESNA in the biological samples (lungs, liver, kidney and brain) were determined. The highest concentration of MESNA was found in plasma. Of all the tissues, the kidney was found to have the highest concentration while the liver had the lowest concentration.

Disodium 2,2'-dithio-bis-ethane sulfonate (BNP7787) is under investigation as a potential new chemoprotector against cisplatin-induced nephrotoxicity. The selective protection of BNP7787 appears to arise from the preferential uptake of the drug in the kidneys, where BNP7787 would undergo intracellular conversion into mesna (2-mercapto ethane sulfonate), which in turn can prevent cisplatin induced toxicities. In the present study, we have investigated whether the reduction of BNP7787 into the reactive compound mesna is restricted to the kidney or whether it can also occur in other organs, cells and physiological compartments, including the cytosolic fraction of the renal cortex, plasma, red blood cells (RBCs), liver and small intestine from rats and several tumors (OVCAR-3, MRI-H-207 and WARD). We also determined whether the endogenous thiols glutathione (GSH) and cysteine and the enzyme systems glutaredoxin and thioredoxin, which are all present in the kidney, can be involved in the BNP7787 reduction. UV detection and micro-HPLC with dual electrochemical detection were used to analyze the various incubation mixtures. Our observations are that, in contrast to plasma, a very large reductive conversion of BNP7787 to mesna was measured in RBC lysate. Intact RBCs, however, did not take up BNP7787. Although BNP7787 could be reduced in cytosol of liver and several tumors, this reduction will not be relevant in vivo, since these tissues do not take up large amounts of BNP7787. Kidney cortex cytosol was, similar to the small intestine cytosol, able to substantially reduce BNP7787 to mesna. The ability to reduce BNP7787 in the presence of the endogenous thiols GSH and cysteine, the glutaredoxin system as well as the thioredoxin system, could at least in part explain the high BNP7787 reductive activity of the kidney cortex cytosol. In conclusion, the high reduction of BNP7787 into mesna in the kidney as well as our earlier observation that the distribution of BNP7787 and mesna was mainly restricted to rat kidney are strong arguments in favor of selective protection of the kidney by BNP7787.

Cellular glutathione (GSH) levels are related to the resistance of tumor cells to platinum and alkylating agents, and depletion of GSH may enhance the activity of these drugs. The pharmacodynamic effects of mesna on depleting plasma cysteine, a GSH precursor, were evaluated in 22 patients as part of a Phase I study. Escalating doses of ifosfamide and mesna were administered; carboplatin was administered to achieve an AUC of 4 mg x min/mL. Plasma samples were collected and assayed by reverse-phase high-performance liquid chromatography (HPLC) for total mesna and total cysteine concentrations at 0, 1, 3, 6, 24, 25, 28, and 48 hours. A one-compartment pharmacokinetic model was fit to the mesna plasma concentrations, using M.A.P. Bayesian estimation (ADAPT II). Pharmacodynamics were evaluated by fitting an inhibitory Emax model to the cysteine concentration data. Both the pharmacokinetic (median R2 = 0.95; range = 0.85-0.98) and pharmacodynamic (median R2 = 0.96; range = 0.74-1.0) models fit the data well. Mean (coefficient of variation [CV%]) mesna pharmacokinetic parameter estimates were as follows: Vss of 15.3 (29) L/m2, CL of 4.6 (29) L/h/m2, and half-life of 2.2 (37) hours. Mean (CV%) pharmacodynamic parameter estimates were as follows: Emax of 31.7 (19) microg/mL and EC50 of 10.3 (52) microg/mL. Mesna produced a rapid, concentration-dependent reduction in plasma cysteine concentrations that could be adequately characterized by an inhibitory Emax pharmacodynamic model. The depletion of plasma cysteine was facilitated by ifosfamide, suggesting a pharmacodynamic interaction between these two agents. Further increases in mesna doses beyond those administered in this study would be unlikely to provide additional benefit.

Purpose: BNP7787 (2',2'-dithio-bis-ethane sulfonate sodium) is a novel protector against cisplatin-induced toxicities. The pharmacokinetics of BNP7787 and its metabolite mesna were investigated in plasma and ascites of a cancer patient. We also evaluated potential pharmacokinetic interactions between BNP7787 and cisplatin., Methods: BNP7787 and mesna were measured as mesna in deproteinized plasma and ascites using high-performance liquid chromatography with an electrochemical detector provided with a wall-jet gold electrode., Results: After the i.v. administration of 41 g/m(2) BNP7787, BNP7787 and mesna had a half-life of 1.5 and 3.4 h, respectively. The AUC( infinity ) of mesna was approximately 8% of the AUC( infinity ) of BNP7787. Coadministration of cisplatin did not appear to influence the plasma concentration-time curves of BNP7787 and mesna. In ascites, approximately 0.02% of the BNP7787 dose was present as mesna, whereas approximately 4% of the dose was present as BNP7787 at the time of the maximum concentration., Conclusions: It can be concluded that the presence of ascites did not have a major impact on the pharmacokinetics of BNP7787 and coadministration of cisplatin did not influence the pharmacokinetics of BNP7787 and mesna.

Sensitive, accurate, and precise assays are described to determine BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate) and its metabolite mesna (sodium 2-mercaptoethane sulfonate) simultaneously in plasma and tissue by micro-high-performance liquid chromatography (HPLC) with dual electrochemical detection. After separation of BNP7787 and mesna by micro-HPLC, the disulfide BNP7787 was reduced to mesna by a reactor cell with a glassy carbon working electrode (-1.6 V versus Hy-REF). At the second electrode, which consisted of a gold wall-jet electrode, the mesna generated from BNP7787 and the mesna already present in the samples were detected (+0.85 V versus Ag/AgCl). The lower limit of quantification (LLQ) of both compounds was 3 microM in plasma and 20 nmol/g in tissue. The dynamic range of the assay in plasma was 3-120 microM for mesna and 15-1200 microM for BNP7787. In tissue, the dynamic range was 20-2000 nmol/g for both compounds. The recovery of mesna from plasma and tissue ranged from 61.4 to 90.5% and 82.7 to 90.2%, respectively, and seemed to be concentration dependent. The recovery of BNP7787 from plasma and tissue was complete (i.e., 101.5 and 96.4%, respectively). The within- and between-day accuracy and precision for the plasma and tissue assay were within 14 and 7%, respectively. The utility of the assay was shown by determination of the stability of mesna and BNP7787 in a kidney sample of a rat and by analysis of plasma samples obtained from a patient receiving 18.4 g/m(2) BNP7787 as a 15-min intravenous infusion., (Copyright 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:1040-1050, 2003)

BNP7787 (2',2'-dithio-bis-ethane sulphonate sodium), a water-soluble disulphide, is chemically and mechanistically different from other sulphur-containing chemoprotective agents. Presently, BNP7787 is under investigation for its protective properties with regard to the side-effects of platinum compounds. In this study, we evaluated BNP7787, mesna and amifostine for their effects on the antitumour activity of platinum compounds. Continuous exposure to BNP7787 did not affect the antiproliferative effects of cisplatin or carboplatin, but the efficacy of both compounds was reduced in the presence of mesna in vitro in two human ovarian cancer cell lines. BNP7787 or amifostine combined with cisplatin or carboplatin given in standard schedules for the treatment of nude mice bearing well-established OVCAR-3 xenografts did not interfere with platinum-induced inhibition of tumour growth. Of interest, BNP7787 or amifostine co-administered with carboplatin was significantly more effective than carboplatin alone (P<0.01). In the presence of amifostine, doses of cisplatin and carboplatin could be safely increased by factors of 1.6 and 1.5, respectively. Unlike in a previous study of BNP7787 in tumour-bearing rats, BNP7787 did not protect against additional weight loss following treatment with higher doses of cisplatin in OVCAR-3-bearing mice. Pharmacokinetics of (mixed) disulphides including BNP7787 and extractable mesna in deproteinised plasma revealed a rapid disappearance of BNP7787 and an AUC(5-60) value of mesna 9-fold lower than that calculated after an equivalent dose of mesna by weight. We can conclude that BNP7787 does not interfere with the antitumour activity of platinum compounds in vitro and in vivo. Clinical trials are underway to evaluate the protection of normal tissues by BNP7787 when combined with cisplatin.

The Pediatric Oncology Group study for metastatic Ewing's sarcoma used amifostine and mesna with the alkylating agents. To determine the fate of combined drug thiols, we measured thiol levels in plasma, red blood cells (RBC), and peripheral blood mononuclear cells (PBMC) of four patients. We also conducted analogous measurements on two patients who received mesna alone and a volunteer's blood following in vitro treatment. Thiols were labeled with monobromobimane, separated on high-pressure liquid chromatography, and detected by fluorescence. Incubation of a volunteer's blood with mesna, WR-1065, or both revealed that cellular uptake of total reducible drug was approximately 10% of plasma level for mesna but approximately 60% for WR-1065. Cellular drugs were mainly the thiol form, whereas half of the plasma drugs were disulfides. Combined incubation with both thiols did not change the extent or form of uptake. WR-1065 and mesna prevented glutathione depletion by 4-hydroperoxycyclophosphamide. Results from patients were similar. WR-1065 and mesna appeared in the cells by the end of the drug infusions, although WR-1065 uptake was more efficient than mesna. The concentration-time profiles of mesna in RBC paralleled those in plasma. Amifostine administration during mesna infusion caused transient increase in mesna levels. Both agents increased blood cysteine and decreased total reducible cysteine. Mesna alone and mesna plus amifostine prevented cellular glutathione depletion. In conclusion, mesna is imported by RBC and PBMC, but less efficiently than WR-1065. When present at equal levels, these thiols do not influence each other's uptake. Adequate dosing of either drug is necessary for protecting the cells from toxic effects of alkylating agents.

The use of 2-chloro-1-methylquinolinium tetrafluoroborate, an ultraviolet tagging reagent, for the ion-pair, reversed-phase high-performance liquid chromatography of mesna in human plasma is reported. In order to achieve this objective optimization of the two-step procedure, derivatization and separation of mesna S-quinolinium derivative from that of other thiols present in plasma and internal standard, was investigated. The derivatization was optimized in terms of pH, reagent excess and time of the reaction, and the mobile phase in terms of ion-pairing reagent concentration, pH, organic modifier content and temperature. Baseline separation was achieved on an analytical Waters Nova-Pak C18 (150x3.9 mm, 5 microm) column with a mobile phase consisting of pH 2.3 0.05 M trichloroacetic acid-acetonitrile (89:11, v/v) pumped at 1.2 ml/min. The peak height ratios of the mesna derivative to that of the internal standard (thiomalic acid) varied linearly with the concentration of the analyte added to normal plasma with a correlation coefficient of 0.9997. The lower limits of detection and quantitation were 40 pmol/ml (0.8 pmol on-column) and 160 pmol/ml (3.2 pmol on-column), respectively. The intra-run imprecision and inaccuracy were from 1.3 to 2.4 and from 1.3 to 2.0%, respectively.

A sensitive and accurate assay was developed and validated to determine BNP7787 (dimesna), a new protector against cisplatin-induced toxicities, and its metabolite mesna in plasma and urine of patients. Both analytes were measured as mesna in deproteinized plasma or in urine diluted with mobile phase using high-performance liquid chromatography with an electrochemical detector provided with a wall-jet gold electrode. The assays for BNP7787 and mesna in deproteinized plasma were linear over the range of 1.6-500 microM and 0.63-320 microM, respectively. In plasma, the mean recovery of BNP7787 over the whole concentration range was 100.6% and of mesna 94.6%. The lower limits of quantitation (LLQs) of BNP7787 and mesna in deproteinized plasma were 1.6 microM and 0.63 microM, respectively. For both compounds the within- and between-day accuracy and precision of the assay was better than 12%. The assays for BNP7787 and mesna in urine were linear over the range of 0.8-1200 microM and 0.63-250 microM, respectively. In urine, the mean recovery of BNP7787 over the whole concentration range was 94.1% and of mesna 93.1%. The LLQ of BNP7787 in urine was 0.8 microM and of mesna 1.6 microM. The within- and between-day accuracy and precision of the assay for BNP7787 and mesna was lower than 15%. The stability of mesna in urine increased with an increasing concentration of mesna, lower temperature and addition of EDTA (1 g/l) and hydrochloric acid (0.2 M). BNP7787 in urine was stable for at least 24 h at temperatures in the range of -20 degrees C up to 37 degrees C and independent of the concentration. The developed assays are currently applied for samples of patients with solid tumors participating in a phase I trial of BNP7787 in combination with cisplatin.

Depletion of cellular glutathione (GSH) enhances the efficacy of many anticancer agents in preclinical systems. Limited published data showing depletion of GSH in vitro and in patients by ifosfamide and/or mesna provided the rationale for a Phase I trial. Ifosfamide and mesna were infused over 24 and 36 h, respectively, at equal daily doses; carboplatin was given after ifosfamide to a target plasma area under the curve of 4 mg x min x ml(-1). Plasma and peripheral WBC thiols were quantitated by high-performance liquid chromatography. The dose of ifosfamide was escalated from 2 to 8 g/m2; the maximum tolerated dose was 6 g/m2. Significant depletion in plasma cysteine and homocysteine, precursors for GSH synthesis, was observed (maximum, 95% to >99% at 8 g/m2). Plasma mesna and cysteine/ homocysteine levels were inversely correlated; nadir levels of cysteine/homocysteine were maintained for several hours after ifosfamide infusion had stopped and while mesna infusion was continuing. In vitro coincubation experiments confirmed that mesna reduces these thiols from disulfides to sulfhydryls, which are readily cleared, as evidenced by the significantly increased rate of excretion of cysteine in urine. In contrast, ifosfamide/mesna treatment caused a moderate depletion of plasma GSH in only 60% of the patients, with a nadir at 24 h and recovery immediately after the end of ifosfamide infusion. The GSH depletion in these patients was not dose related. The profile of GSH recovery in plasma after ifosfamide and the fact that mesna could not reduce GSH disulfides in vitro suggest that the observed GSH depletion in plasma in 60% of the patients may be related to direct reactions of GSH with ifosfamide metabolites and/or mesna. Our results indicate that mesna is a modulator of GSH precursors and that a prolonged infusion of mesna may be required to achieve GSH precursor starvation and the consequent GSH depletion in cells.

The chemotherapeutic benefit of synergistic drug combinations and higher drug dosages has generated interest in the application of these regimens to cancer patients. A major obstacle in the application of these strategies to the treatment of cancer is the dose-limiting toxicities of drug combinations. Sodium 2-mercaptoethane-sulfonate (mesna), a chemoprotective drug, may reduce the nephrotoxicity of carboplatin [CBDCA, paraplatin, JM-8, cis-diammine (1,1-cyclobutane dicarboxylato) platinum II] when administered in combination chemotherapy. The purpose of this study was to evaluate, compare and contrast in vitro the interaction of mesna with carboplatin in aqueous solution, human plasma and urine. Carboplatin and mesna were incubated separately and together at clinically relevant concentrations in plasma and urine. The concentration of carboplatin was assayed by HPLC, and the decay of carboplatin alone and in combination with mesna was compared. The incubation of carboplatin with mesna in human plasma up to 8 days did not result in a statistically significant interaction: the half-life of carboplatin in plasma when it was combined with mesna was 1.62 +/- 0.08 (SE) days compared to 1.85+/- 0.04 (SE) days for carboplatin by itself. The incubation of drugs in fresh human urine up to 15 days gave a half-life of 3.43+/- 0.8 (SE) days for carboplatin alone and 2.78 +/- 0.7 (SE) days for carboplatin when it was combined with mesna. Our results show that carboplatin and mesna do not significantly interact in plasma. Although a statistically significant difference between the half-life of carboplatin and the half-life of the carboplatin/mesna combination is detected in urine, it is not likely to be clinically significant, as there is no significant interaction detected in the first 48 h). It is thus unlikely that mesna would substantially affect the pharmacokinetics of carboplatin when both are given together to patients as part of combination chemotherapy regimens.

We describe in this report an expedient and accurate liquid chromatographic method for measurement of mesna and dimesna in plasma and urine. The separation of mesna and the internal standard (p-aminobenzoic acid, IS) was achieved on a 10-microns, 8 mm (i.d.) x 10-cm C18-Resolve cartridge in conjunction with radial compression system. An aqueous solution of sodium citrate (0.1 M), tetrabutyl ammonium phosphate (0.001 M), and triethylamine (1:10,000, vol/vol), adjusted to pH 5 with 85% phosphoric acid was used at a flow rate of 2 ml/min as a mobile phase. The compounds were detected in the effluent electrochemically at +450 mV. After an appropriate amount of IS was added, the plasma sample (100 microliters or fraction thereof) was deproteinized with an equal volume of 0.0825 M sulfuric acid containing sodium hexametaphosphate (1.25% wt/vol), whereas urine was diluted 1:50 with water and mixed 1:1 with an aqueous solution of sodium hexametaphosphate (1.25% wt/vol). Dimesna was reduced back to mesna with sodium borohydride before analysis of the total mesna. The peak height ratio (drug/IS) varied linearly with the concentration, and the correlation coefficient was > 0.992 for both mesna and dimesna. The intrarun precision at different concentrations of mesna was equally good and the coefficient of variation was consistently < 4.5%. No interference from endogenous substances or any concomitantly used drug was observed. This assay is currently being used for measurement of mesna and dimesna in plasma of bone marrow recipients who receive high doses of cyclophosphamide.

The sulfhydryl status of cells, particularly the intracellular concentration of glutathione, is a critical determinant of the response of tumor and normal cells to cytostatic drugs. Recent data indicate that the administration of mercaptoethane sulfonate (mesna), which is often combined with ifosfamide, markedly decreases the circulating concentration of total cysteine and could thereby influence the response of the organism to the cytotoxic effects of chemotherapy. The aim of the present study was to assess the effects of the combination of ifosfamide/mesna on sulfhydryl and disulfide homeostasis in tumor patients. Ifosfamide was infused into 14 patients with advanced sarcoma for 5 days at a dose of 2.4-3.2 g/m2 per day together with mesna. The plasma concentrations of total mesna, cysteine, glutathione, and homocysteine were measured before and on days 1 and 6 of the first course of ifosfamide/mesna therapy and prior to the next course of chemotherapy, and the urinary excretion of cysteine and mesna was monitored daily using a high-performance liquid chromatography (HPLC) method. Ifosfamide/mesna resulted in a marked depletion of circulating total cysteine, i.e., cysteine, cystine, and cysteine mixed disulfides [from 245 +/- 36 to 50 +/- 14 nmol/ml (mean +/- 95% CI) on day 6], total glutathione (from 6.9 +/- 1.1 to 2.5 +/- 1.1 nmol/ml), and total homocysteine (from 12.3 +/- 2.1 to 1.4 +/- 1.1 nmol/ml). The values returned to baseline levels prior to the next course of chemotherapy. The urinary excretion of cysteine increased significantly from 0.28 to 1.82 mmol/day on the 1st day, whereupon it returned toward baseline. An average of 62% +/- 6% of the delivered dose of mesna was recovered in urine. The combination of ifosfamide/mesna results in depletion of circulating total cysteine, glutathione, and homocysteine. This marked derangement of sulfhydryl and disulfide homeostasis could modulate the efficacy and toxicity of ifosfamide/mesna therapy.

The influence of disodium 2-mercaptoethane sulfonate disulfide (mesna, Uromitexan) and sodium 2-mercaptoethane sulfonate (dimesna) on the carrier mediated exchange of 35S-sulfate in human red blood cells was investigated in vitro in order to contribute to the understanding of pharmakokinetics and organospecific action of mesna. Countertransport indicated uptake of mesna in washed red blood cells by the carrier. In contrast, dimesna inhibited the transport of sulfate in a competitive manner. However, when 35S-sulfate uptake into red cells was studied with whole blood, addition of mesna was found to be inhibitory, which was caused by its rapid conversion to dimesna by plasma components. It is concluded that conversion of the anion carrier substrate mesna into the inhibitor dimesna is the reason that mesna or dimesna cannot be detected in red blood cells in vivo.

[14C]-Mesna (sodium 2-mercaptoethanesulphonate) has a short serum t1/2 (about 16.5 min) and is excreted in the urine. Within 24 h approx. 77% of the administered dose appeared in the urine. It is bound to serum albumin and immunoglobulins. Total serum protein binding is about 9.7% of the total amount present in serum. [14C]-mesna + [14C]-dimesna (bis[2-mercaptoethane sulphonate]) are present in the blood stream, and so are found in the body organs at low concentration, however, localisation of radioactivity occurs in the kidneys. The binding of [14C]-mesna to proteins and the localisation of [14C]-mesna or [14C]-dimesna in the kidneys are discussed in the context of the cell killing efficacy of the oxazaphosphorines.