Dimesna

Dimesna is an inhibitor of OAT family with IC50 value of 636 μM, 390 μM, and 590 μM for OAT1, OAT3, and OAT4, respectively [1].
OATs (organic anion transporters) involve in many life processes, like elimination of a variety of endogenous substances, xenobiotics and their metabolites from the body. It has been shown that OATs play an important role in mediating the renal and hepatic elimination of organic anions using molecular cloning method [2].
Dimesna is an OAT inhibitor and often used as an uroprotective drug. When tested with renal tubular cell line LLC-PK1, in combination with IF metabolites, dimesna treatment exerted uroprotective action [3]. When tested with human renal proximal tubule HK-2 cells, dimesna was detected to accumulate in cells and played an important role in reducing chemotherapy-induced toxicities [4].
References:
[1].Cutler, M.J., et al., In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna. J Clin Pharmacol, 2012. 52(4): p. 530-42.
[2].Roth, M., A. Obaidat, and B. Hagenbuch, OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol, 2012. 165(5): p. 1260-87.
[3].Mohrmann, M., et al., Dithio-bis-mercaptoethanesulphonate (DIMESNA) does not prevent cellular damage by metabolites of ifosfamide and cyclophosphamide in LLC-PK1 cells. Pediatr Nephrol, 1994. 8(4): p. 458-65.
[4].Hausheer, F.H., et al., Accumulation of BNP7787 in human renal proximal tubule cells. J Pharm Sci, 2011. 100(9): p. 3977-84.

Vibrational spectroscopic studies of mesna and dimesna.[Pubmed:12736065]

Spectrochim Acta A Mol Biomol Spectrosc. 2003 Jun;59(8):1791-8.

Raman, and infrared spectra of mesna and Dimesna have been collected in the present spectroscopic studies. Based on the group frequencies, relative intensities and Raman depolarization measurements, some vibrational assignments have been suggested. For both mesna and Dimesna, at least two rotational conformers have been identified. Adsorption behavior was investigated from the recorded surface-enhanced Raman scattering (SERS) spectra. It was found that both mesna and Dimesna adsorbed as thiolate on silver sol particles with the cleavage of the S-H bond in mesna and the S-S bond in Dimesna. For the adsorbed thiolate, two conformers existed in the adsorption state.

Quantification of BNP7787 (dimesna) and its metabolite mesna in human plasma and urine by high-performance liquid chromatography with electrochemical detection.[Pubmed:11334343]

J Chromatogr B Biomed Sci Appl. 2001 Apr 5;753(2):293-302.

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.

Enzymatic and non-enzymatic mechanisms of dimesna metabolism.[Pubmed:25488427]

Amino Acids. 2015 Mar;47(3):511-23.

The chemical reduction of the disulfide homodimer Dimesna to its constituent mesna moieties is essential for its mitigation of nephrotoxicity associated with cisplatin and ifosfamide anticancer therapies and enhancement of dialytic clearance of the cardiovascular risk factor homocysteine. The objective of this study was to investigate potential enzymatic and non-enzymatic mechanisms of intracellular Dimesna reduction. Similar to endogenous intracellular disulfides, Dimesna undergoes thiol-disulfide exchange with thiolate anion-forming sulfhydryl groups via the two-step SN2 reaction. Determination of equilibrium constants of Dimesna reduction when mixed with cysteine or glutathione provided a mechanistic explanation for dramatic cysteine and homocysteine depletion, but sparing of the endogenous antioxidant glutathione, previously observed during mesna therapy. Dimesna was reduced by recombinant enzymes of the thioredoxin system; however, oxidation of NADPH by the glutaredoxin system was only observed in the presence of combined Dimesna and reduced glutathione, suggesting formation of oxidized glutathione following an initial non-enzymatic reduction of Dimesna. Production of mesna by enzymatic and non-enzymatic mechanisms in HeLa cell lysate following Dimesna incubation was demonstrated by a loss in mesna production following protein denaturation and prediction of residual non-enzymatic mesna production by mathematical modeling of thiol-disulfide exchange reactions. Reaction modeling also revealed that mixed disulfides make up a significant proportion of intracellular thiols, supporting their role in providing additional nephroprotection, independent of direct platinum conjugation.

In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna.[Pubmed:21505084]

J Clin Pharmacol. 2012 Apr;52(4):530-42.

Mesna and its dimer, Dimesna, are coadministered for mitigation of ifosfamide- and cisplatin-induced toxicities, respectively. Dimesna is selectively reduced to mesna in the kidney, producing its protective effects. In vitro screens of uptake and efflux transporters revealed saturable uptake by renal organic anion transporters OAT1, OAT3, and OAT4. Efflux transporters breast cancer resistance protein; multidrug and toxin extrusion 1 (MATE1); multidrug resistance proteins MRP1, MRP2, MRP4, and MRP5; and P-glycoprotein (Pgp) significantly reduced Dimesna accumulation. Further investigation demonstrated that renal apical efflux transporters MATE1, MRP2, and Pgp were also capable of mesna efflux. Administration of OAT inhibitor probenecid to healthy subjects significantly increased combined mesna and Dimesna plasma exposure (91% +/- 34%) while decreasing the renal clearance due to net secretion (67.0% +/- 12.7%) and steady-state volume of distribution (45.2% +/- 13.4%). Thus, the kidney represents a significant sink of total mesna, whereas function of renal drug transporters facilitates clearance in excess of glomerular filtration rate and likely the presence of active mesna in the urine. Loss of renal transporter function due to genetic variability or drug-drug interactions may decrease the efficacy of chemoprotectants, increasing the risk of ifosfamide- and cisplatin-induced toxicities.