digitoxin and Renal-Insufficiency

Digoxin, which is one of the most commonly prescribed drugs for the treatment of heart failure, is mainly eliminated from the circulation by the kidney. P-glycoprotein is well characterized as a digoxin pump at the apical membrane of the nephron. However, little is known about the transport mechanism at the basolateral membrane. We have isolated an organic anion transporter (OATP4C1) from human kidney. Human OATP4C1 is the first member of the organic anion transporting polypeptide (OATP) family expressed in human kidney. The isolated cDNA encodes a polypeptide of 724 aa with 12 transmembrane domains. The genomic organization consists of 13 exons located on chromosome 5q21. Its rat counterpart, Oatp4c1, is also isolated from rat kidney. Human OATP4C1 transports cardiac glycosides (digoxin, K(m) = 7.8 microM and ouabain, K(m) = 0.38 microM), thyroid hormone (triiodothyronine, K(m) = 5.9 microM and thyroxine), cAMP, and methotrexate in a sodium-independent manner. Rat Oatp4c1 also transports digoxin (K(m) = 8.0 microM) and triiodothyronine (K(m) = 1.9 microM). Immunohistochemical analysis reveals that rat Oatp4c1 protein is localized at the basolateral membrane of the proximal tubule cell in the kidney. These data suggest that human OATP4C1/rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.

Topics: Amino Acid Sequence; Animals; Base Sequence; Cell Line; Cloning, Molecular; Digoxin; DNA, Complementary; Dogs; Female; Humans; Kidney; Kinetics; Male; Molecular Sequence Data; Organic Anion Transporters; Phylogeny; Rats; Recombinant Proteins; Renal Insufficiency; RNA, Messenger; Sequence Homology, Amino Acid; Tissue Distribution; Transfection

Topics: Acute Kidney Injury; Digitalis; Digitalis Glycosides; Glomerulonephritis; Pyelonephritis; Renal Insufficiency; Toxicology

Topics: Acute Kidney Injury; Blood Pressure; Carbohydrate Metabolism; Chemical Phenomena; Chemistry; Coronary Disease; Digitalis; Digitalis Glycosides; Heart Rate; Mitral Valve Stenosis; Nephritis; Pulse; Renal Insufficiency; Strophanthins; Toxicology

Topics: Acute Kidney Injury; Adolescent; Anemia, Hemolytic; Antistreptolysin; Blood Transfusion; Bone Marrow Examination; Child; Dialysis; Diet; Diet Therapy; Digitalis; Electrocardiography; Electroencephalography; Electrophoresis; Erythrocytes; Heart Failure; Hemolytic-Uremic Syndrome; Humans; Infant; Kidney; Neurologic Manifestations; Pathology; Prednisone; Renal Dialysis; Renal Insufficiency; Statistics as Topic; Thrombocytopenia; Uremia; Water-Electrolyte Balance