Differential changes in functional activity of organic cation transporters in rats with uranyl nitrate-induced acute renal failure
- Authors
- Maeng, Han-Joo; Shim, Won-Sik; Ahn, Sun-Joo; Yu, Sang-Soo; Kim, Dae-Duk; Shim, Chang-Koo; Chung, Suk-Jae
- Issue Date
- Aug-2012
- Publisher
- PHARMACEUTICAL SOC KOREA
- Keywords
- Uranyl nitrate-induced acute renal failure (UN-ARF); Organic cation; Plasma; rOCT2; LLC-PK1
- Citation
- ARCHIVES OF PHARMACAL RESEARCH, v.35, no.8, pp.1441 - 1448
- Journal Title
- ARCHIVES OF PHARMACAL RESEARCH
- Volume
- 35
- Number
- 8
- Start Page
- 1441
- End Page
- 1448
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/16249
- DOI
- 10.1007/s12272-012-0814-3
- ISSN
- 0253-6269
- 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 mu mol/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.
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