title: In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, The University of Western Ontario, London, Ontario, Canada. murray.cutler@dal.ca
authors.forename: M J
authors.initials: MJ
authors.lastname: Cutler
authors.forename: B L
authors.initials: BL
authors.lastname: Urquhart
authors.forename: T J
authors.initials: TJ
authors.lastname: Velenosi
authors.forename: H E
authors.initials: HE
authors.lastname: Meyer Zu Schwabedissen
authors.forename: G K
authors.initials: GK
authors.lastname: Dresser
authors.forename: B F
authors.initials: BF
authors.lastname: Leake
authors.forename: R G
authors.initials: RG
authors.lastname: Tirona
authors.forename: R B
authors.initials: RB
authors.lastname: Kim
authors.forename: D J
authors.initials: DJ
authors.lastname: Freeman
mesh_terms: D000328:Adult; D005260:Female; D005919:Glomerular Filtration Rate; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D015080:Mesna / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D020011:Protective Agents / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D020011:Protective Agents; C027032:2,2'-dithiodiethanesulfonic acid; D015080:Mesna; D011339:Probenecid