title: Renal uptake of substrates for organic anion transporters Oat1 and Oat3 and organic cation transporters Oct1 and Oct2 is altered in rats with adenine-induced chronic renal failure.
abstract: Chronic renal failure (CRF) leads to decreased drug renal clearance and glomerular filtration rate. However, little is known about renal tubular excretion and reabsorption in CRF. We examined transport activity of renal transporters using rats with adenine-induced CRF. We examined the effect of adenine-induced CRF on mRNA level, protein expression of transporters expressed in kidney by real-time polymerase chain reaction, and western blotting. In vivo kidney uptake clearances of benzylpenicillin and metformin, which are typical substrates for renal organic anion transporters Oat1 and Oat3 and organic cation transporters Oct1 and Oct2, respectively, were evaluated. Protein and mRNA expression levels of Oat1, Oat 3, Oct1, and Oct2 were significantly decreased in adenine-induced CRF rats. On the contrary, levels of P-glycoprotein and Mdr1b mRNA were significantly increased in adenine-induced CRF rats. The mRNA expression levels of Oatp4c1, Mate1, Urat1, Octn2, and Pept1 were significantly decreased. Kidney uptake clearance of benzylpenicillin and that of metformin were significantly decreased in adenine-induced CRF rats. Also, serum from CRF rats did not affect Oat1, Oat3, Oct1, and Oct2 function. In conclusion, our results indicate that adenine-induced CRF affects renal tubular handling of drugs, especially substrates of Oat1, Oat3, Oct1, and Oct2.
authors.affiliation: Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Komazawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hidaka
authors.forename: Jiro
authors.initials: J
authors.lastname: Ogura
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D000225:Adenine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D001835:Body Weight; D015870:Gene Expression; D007004:Hypoglycemic Agents / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008687:Metformin / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D010400:Penicillin G / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D044967:Serum / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D007004:Hypoglycemic Agents; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger; C100590:Slc22a2 protein, rat; C421043:Slc22a6 protein, rat; C114338:organic anion transport protein 3; D008687:Metformin; D000225:Adenine; D010400:Penicillin G