Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr. David J. Freeman

Abstract

In the early 1980s, significant advancement in the safety of ifosfamide therapy was achieved by co-administrating mesna (sodium 2-mercaptoethane sulfonate) to prevent dose-limiting hemorrhagic cystitis. Mesna exerts its protective effect within the urine, where its free sulfhydryl group is able to conjugate cytotoxic metabolites. Within the circulation, however, mesna exists primarily as its inactive disulfide, dimesna. Dimesna is currently undergoing clinical development as a prodrug (BNP7787) to treat cisplatin-induced nephrotoxicity. Remarkably, chemoprotection is achieved without attenuation of efficacy of co-administered anti-cancer agents. This is widely attributed to the kidney-specific disposition and stability of dimesna.

We sought to evaluate the role of drug transporters in the disposition of dimesna. In vitro screens of uptake and efflux transporters identified putative mechanisms of apical and basolateral uptake of dimesna and subsequent secretion of mesna into renal tubules. Administration of the renal drug transporter inhibitor probenecid to healthy subjects significantly increased combined mesna and dimesna plasma exposure while decreasing the renal clearance due to secretion and steady-state volume of distribution.

Chemical reduction of dimesna to mesna is essential for the mitigation of ifosfamide- and cisplatin-induced toxicities. In vitro, reduction of dimesna was facilitated by redox enzymes of the thioredoxin and glutaredoxin systems and also by non-enzymatic thiol-disulfide exchange with cysteine and glutathione. These findings supported the further investigation of mesna as a thiol exchange agent to lower the toxic endogenous thiol amino acid homocysteine (Hcy).

Increased plasma total homocysteine (tHcy) is a graded, independent risk factor for the development of atherosclerosis and thrombosis. Over 90% of patients with end-stage renal disease (ESRD) have elevated plasma tHcy. Previous studies have expanded the use of mesna to exchange with albumin-bound Hcy, thereby enhancing its dialytic clearance. Although an initial pilot study of 12 mg/kg intravenous mesna administered predialysis caused a significant decrease in plasma tHcy compared to placebo, prolonged treatment had no effect on plasma tHcy.

Successful therapeutic uses of mesna and dimesna are likely due to their unique disposition by renal drug transporters and thiol-disulfide redox equilibrium. Loss of renal transporter function due to disease, drug-drug interactions, or genetic variability may decrease their therapeutic efficacy.


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