title: Localization of heparin and low-molecular-weight heparin in the rat kidney.
abstract: Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are cleared, at least in part, by the kidneys through a poorly understood process. This study was undertaken to explore the mechanism of renal clearance of these drugs. Rats were given fluorescein-5-isothiocyanate (FITC)-labeled UFH or LMWH intravenously. At intervals after injection, rats were euthanized and the kidneys were harvested and subjected to immunohistochemical analysis and fluorescence microscopy. Both UFH and LMWH were localized to renal tubular cells and no immunoperoxidase staining or fluorescence was detected in glomeruli. Autoradiography demonstrated similar intracellular distribution of radio-labeled UFH suggesting that this phenomenon is independent of the method used to label heparin. Fluorescence in the tubules increased as a function of time after UFH injection, but reached a plateau after LMWH injection suggesting that the rate of renal tubular uptake depends on the molecular size of the heparin. When administered prior to FITC-labeled UFH or LMWH, probenecid, a renal organic anion inhibitor, decreased the renal tubular uptake of the heparins, whereas cimetidine, a renal organic cation inhibitor, had no effect. These findings suggest that renal excretion of UFH and LMWH primarily reflects tubular uptake via an organic anion transport mechanism.
authors.affiliation: Department of Pathology, McMaster University, Henderson Research Centre, Hamilton, Ontario, Canada, L8V 1C3. younged@hhsc.ca
authors.forename: Edward
authors.initials: E
authors.lastname: Young
authors.forename: Vivian
authors.initials: V
authors.lastname: Douros
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Podor
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Shaughnessy
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
mesh_terms: D000818:Animals; D000838:Anions / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D016650:Fluorescein-5-isothiocyanate; D006493:Heparin / Q000493:pharmacokinetics*; D006495:Heparin, Low-Molecular-Weight / Q000493:pharmacokinetics*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008970:Molecular Weight; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000838:Anions; D006495:Heparin, Low-Molecular-Weight; D006493:Heparin; D016650:Fluorescein-5-isothiocyanate; D011339:Probenecid