title: Transporters involved in renal excretion of N-carbamoylglutamate, an orphan drug to treat inborn n-acetylglutamate synthase deficiency.
abstract: Inborn defects in N-acetylglutamate (NAG) synthase (NAGS) cause a reduction of NAG, an essential cofactor for the initiation of the urea cycle. As a consequence, blood ammonium concentrations are elevated, leading to severe neurological disorders. The orphan drug N-carbamoylglutamate (NCG; Carbaglu), efficiently overcomes NAGS deficiency. However, not much is known about the transporters involved in the uptake, distribution, and elimination of the divalent organic anion NCG. Organic anion-transporting polypeptides (OATPs) as well as organic anion transporters (OATs) working in cooperation with sodium dicarboxylate cotransporter 3 (NaDC3) accept a wide variety of structurally unrelated drugs. To test for possible interactions with OATPs and OATs, the impact of NCG on these transporters in stably transfected human embryonic kidney-293 cells was measured. The two-electrode voltage-clamp technique was used to monitor NCG-mediated currents in Xenopus laevis oocytes that expressed NaDC3. Neither OATPs nor OAT2 and OAT3 interacted with NCG, but OAT1 transported NCG. In addition, NCG was identified as a high-affinity substrate of NaDC3. Preincubation of OAT4-transfected human embryonic kidney-293 cells with NCG showed an increased uptake of estrone sulfate, the reference substrate of OAT4, indicating efflux of NCG by OAT4. In summary, NaDC3 and, to a lesser extent, OAT1 are likely to be responsible for the uptake of NCG from the blood. Efflux of NCG across the luminal membrane into the tubular lumen probably occurs by OAT4 completing renal secretion of this drug.
authors.affiliation: Institute of Systemic Physiology and Pathophysiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schwob
authors.affiliation: Institute of Systemic Physiology and Pathophysiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Hagos
authors.affiliation: Institute of Systemic Physiology and Pathophysiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Burckhardt
authors.affiliation: Institute of Systemic Physiology and Pathophysiology, University Medical Center Göttingen, Göttingen, Germany birgitta.burckhardt@med.uni-goettingen.de.
authors.forename: Birgitta C
authors.initials: BC
authors.lastname: Burckhardt
mesh_terms: D051046:Amino-Acid N-Acetyltransferase; D000818:Animals; D029382:Dicarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008564:Membrane Potentials; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D065667:Renal Elimination; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D056806:Urea Cycle Disorders, Inborn / Q000188:drug therapy* / Q000201:enzymology; D014982:Xenopus laevis
chemical_list: D029382:Dicarboxylic Acid Transporters; D005971:Glutamates; D027362:Organic Anion Transport Protein 1; D029363:Organic Anion Transporters, Sodium-Dependent; C092524:SLC13A2 protein, human; C470492:SLC13A5 protein, human; D027981:Symporters; C006895:N-carbamylglutamate; D051046:Amino-Acid N-Acetyltransferase
keywords: dicarboxylates; hyperammonemia; organic anion transport