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The orphan drug carbaglu is a substrate of the sodium dicarboxylate transporter 3 (896.8)
Author(s) -
Burckhardt Birgitta,
Schwob Elisabeth,
Hagos Yohannes,
Burckhardt Gerhard
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.896.8
Subject(s) - chemistry , transporter , sodium , urea , organic anion transporter 1 , urea cycle , pharmacology , organic anion transporting polypeptide , biochemistry , medicine , endocrinology , biology , amino acid , arginine , gene , organic chemistry
Inborn defects in the carbamoylphosphate synthase 1 (CPS1) cause a reduction of N ‐acetylglutamate (NAG), an essential cofactor for the function of the urea cycle, and consequently elevated blood levels of the neurotoxic ammonia. N ‐carbamoylglutamate (carglumic acid, carbaglu®, NCG) is a structural analog of NAG that can substitute for NAG on CPS1, thereby reactivating the urea cycle and finally reducing blood ammonia levels. The renal clearance of NCG exceeds the glomerular filtration rate suggesting an active secretion process in kidney proximal tubules. The kidneys are known to express organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs). OATs work in cooperation with sodium‐dicarboxylate transporters (NaDCs) thereby mediating the exit of many drugs. The impact of NCG on several human OATPs, OATs, and NaDCs stably transfected in HEK293 cells was tested. From the transporters tested, OAT1, OATP1B3, and NaDC3 interacted with NCG. Sodium‐ and concentration‐dependent NCG‐mediated currents were measured in Xenopus laevis oocytes expressing NaDC3. NCG was identified as a high affinity substrate of NaDC3 with a K M of 27.5 µM. This value equals the plasma concentration of succinate, the lead substance of NaDC3 and as well as the plasma concentration of patients treated with NCG. Competition of succinate and NCG on NaDC3 may result in reduced renal clearance of drugs.