title: Differential changes in functional activity of organic cation transporters in rats with uranyl nitrate-induced acute renal failure.
abstract: We studied the impact of experimental kidney failure on the pharmacokinetics of a model organic cation and investigated the underlying mechanism(s) of the organic cation transporters. The systemic pharmacokinetics and tissue distribution of triethylmethylammonium (TEMA), a model organic cation, were characterized after intravenous doses of 0.3-30 μmol/kg in rats with or without uranyl nitrate-induced acute renal failure (UN-ARF). To study the effect of endogenous substrates in plasma from UN-ARF rats on organic cation transport, rOCT- or rOCT2-dependent uptake of tetraethylammonium (TEA) was studied in rOCT1-transfected or rOCT2-transfected LLC-PK1 cells, respectively. As a result, the AUC for TEMA was increased, probably because of decreased total clearance, and the tissue-to-plasma concentration ratio (T/P ratio) of TEMA was unchanged in the liver but decreased significantly in the kidneys of UN-ARF rats. In vitro, the uptake of TEA was decreased significantly by adding UN-ARF plasma, compared with control plasma, in rOCT2-overexpressing LLC-PK1 cells, but not in rOCT1-overexpressing LLC-PK1 cells. These observations suggest that the induction of UN-ARF leads to an accumulation of endogenous organic cation(s), probably rOCT2 substrate(s), in the plasma, thereby affecting the TEMA pharmacokinetics and distribution to the kidneys in rats.
authors.affiliation: College of Pharmacy, Inje University, Gyeongnam, 621-749, Korea.
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Shim
authors.forename: Sun-Joo
authors.initials: SJ
authors.lastname: Ahn
authors.forename: Sang-Soo
authors.initials: SS
authors.lastname: Yu
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.forename: Chang-Koo
authors.initials: CK
authors.lastname: Shim
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
mesh_terms: D058186:Acute Kidney Injury / Q000503:physiopathology*; D061605:Administration, Intravenous; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D018374:LLC-PK1 Cells; D008099:Liver / Q000378:metabolism; D008297:Male; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D014018:Tissue Distribution; D014162:Transfection; D014502:Uranyl Nitrate / Q000633:toxicity
chemical_list: D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D000644:Quaternary Ammonium Compounds; C100590:Slc22a2 protein, rat; D014502:Uranyl Nitrate; C043900:triethylmethylammonium