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Pharmacokinetics and Therapeutic Uses of Mesna

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Pharmacokinetics and Therapeutic Uses of Mesna Western University Scholarship@Western Electronic Thesis and Dissertation Repository November 2010 Pharmacokinetics and Therapeutic Uses of Mesna Murray J. Cutler The University of Western Ontario Supervisor Dr. David J. Freeman The University of Western Ontario Graduate Program in Pharmacology and Toxicology A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Murray J. Cutler 2010 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Pharmacology Commons Recommended Citation Cutler, Murray J., "Pharmacokinetics and Therapeutic Uses of Mesna" (2010). Electronic Thesis and Dissertation Repository. 28. https://ir.lib.uwo.ca/etd/28 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. PHARMACOKINETICS AND THERAPEUTIC USES OF MESNA (Spine Title: Pharmacokinetics and Therapeutic Uses of Mesna) (Thesis Format: Integrated-Article) By Murray J. Cutler Department of Physiology and Pharmacology Graduate Program In Pharmacology and Toxicology Submitted in partial fulfillment of the requirement for the degree of Doctor of Philosophy School of Graduate and Postdoctoral Studies The University of Western Ontario London, Ontario November, 2010 © Murray J. Cutler, 2010 THE UNIVERSITY OF WESTERN ONTARIO SCHOOL OF GRADUATE AND POSTDOCTORAL STUDIES CERTIFICATE OF EXAMINATION Supervisor Examiners ______________________________ ______________________________ Dr. David Freeman Dr. Timothy Renault ______________________________ Supervisory Committee Dr. James Koropatnick ______________________________ ______________________________ Dr. Subrata Chakrabarti ______________________________ ______________________________ Dr. Andrea Edginton The thesis by Murray John Cutler entitled: Pharmacokinetics and Therapeutic Uses of Mesna is accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Date__________________________ _______________________________ Chair of the Thesis Examination Board ii 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). iii 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. KEYWORDS Mesna, Dimesna, Transporters, Thiol-disulfide exchange, Homocysteine, End-Stage Renal Disease, Pharmacokinetics iv CO-AUTHORSHIP Versions of chapters two and three of this thesis are undergoing revision prior to submission for publication. Chapter four has been published as: Blood Purification. 2009;27(3):306-10. Epub 2009 Mar 9. Mesna for the treatment of hyperhomocysteinemia in hemodialysis patients. Cutler MJ, Urquhart BL, Freeman DJ, Spence JD, House AA. Murray J. Cutler wrote the initial draft of all manuscripts, but received considerable aid with the experimental work and final manuscript preparation from colleagues and supervisors as follows. CHAPTER 2: Murray J. Cutler, Bradley L. Urquhart, Thomas J. Velenosi, Henriette E. Meyer zu Schwabedissen, George K. Dresser, Rommel G. Tirona, Richard B. Kim, David J. Freeman. IN VITRO AND IN VIVO ASSESSMENT OF THE ROLE OF ORGANIC ANION TRANSPORTERS IN THE DISPOSITION OF MESNA AND DIMESNA Drs. Urquhart and Meyer zu Schwabedissen aided in experimental design and execution, and manuscript preparation. Thomas Velenosi helped with drug analysis. Dr. Dresser provided physicals to all subjects. Drs. Freeman, Kim, and Tirona supervised the project and aided in manuscript preparation. Erin Brouwer is credited with the artistic production of Figure 2.6. CHAPTER 3: Murray J. Cutler, Thomas J. Velenosi, David J. Freeman. ENZYMATIC AND NON-ENZYMATIC MECHANISMS OF DIMESNA METABOLISM Thomas Velenosi aided in experimental design and execution. Dr. Freeman supervised the project and aided in manuscript preparation. CHAPTER 4: Murray J. Cutler, Bradley L. Urquhart, David J. Freeman, J. David Spence, Andrew A. House. MESNA FOR THE TREATMENT OF HYPERHOMOCYSTEINEMIA IN HEMODIALYSIS PATIENTS Dr. House recruited all patients and aided in experimental design and manuscript preparation. Drs. Spence and Urquhart aided in experimental design and manuscript preparation. Dr. Freeman supervised the project and aided in experimental design and manuscript preparation. v DEDICATION To Grandpa vi ACKNOWLEDGEMENTS Over the past decade I’ve been exceedingly fortunate to share fun, food, and research with members, both past and present, of ‘Riederville’ and the ‘Kim Lab’. Michael Knauer, you’ve got all the talents to be a great PI, and your golf game is already ‘pretty OK’. Marianne DeGorter, I’ve no doubt that your hard work and intellect will continue to elevate you to scientific excellence. To my friends of the Society of Automotive Engineers for giving me a new perspective on problem solving. ERTW. Thanks to Dr. Jane Tucker for having the patience to teach me the foundations of cellular biology. Dr. Michael Rieder, I’ll always carry your erudite teachings of the ways of (scientific) war and victory in Grad School. Veni, vidi, vici. Dr. Jack Bend, you are a model of professionalism; I’m truly privileged to count you amongst my advisors. Dr. Peter Chidiac, you’ve always given me thoughtful insight into the art of scientific methods and communication. Dr. Andrew House, your kind support and enthusiasm for scientific investigation have been invaluable to me, both in the clinic, and in the lab. Timely completion of this work would not have been possible, and not nearly as much fun, had it not been for the dedication of young pharmacologists Thomas Velenosi and Ankur Bodalia. Tom, I’ve no doubt your keen sense of humour and understanding of the scientific method will bring you great success in Dr. Urquhart’s lab and beyond. Ankur, you’re a valuable asset to the Freeman Lab; your curiosity and tenacity will lead you to a bright future in science. vii To my best friend, Derek Bone, thanks for your collegiality and commiserations; without you Grad School would have been a lonely journey. I wish I could quit you. Here’s to many years of collaboration to come! Thanks to everyone who has made our clinical research possible. To Linda Asher, for your pragmatic approach to clinical research. I’m grateful, both as a researcher and volunteer, for your thoughtfulness and compassion in the clinic. To Ruth Bullas, MaryJeanne Edgar, and the rest of the Nephrology Clinical Research Group for your help and dedication. To David Demelo for your ingenuity and willingness to always lend a hand, even while keeping an entire dialysis unit running! To Dr. Edna Choo, I can’t thank you enough for the opportunities you gave me during my time at Genentech. I’m incredibly grateful for your depth of scientific knowledge, keen management, gracious hospitality, and above all, friendship. My time spent under your management was some of the best of my graduate career. Part of me will always long to return to San Francisco. Jason Boggs, your honesty, friendship, and perspective helped me choose my path as a scientist.
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