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Differential changes in functional activity of organic cation transporters in rats with uranyl nitrate-induced acute

Han-Joo Maeng1, Won-Sik Shim, Sun-Joo Ahn

  • 1College of Pharmacy, Inje University, Gyeongnam, 621-749, Korea.

Archives of Pharmacal Research
|September 4, 2012
PubMed

Insights

Kidney failure in rats alters the body

Area of Science:

  • Pharmacology and Toxicology
  • Renal Physiology
  • Drug Metabolism and Transport

Background:

  • Organic cation transporters play a crucial role in the excretion and distribution of various endogenous and exogenous compounds.
  • Acute renal failure (ARF) can significantly alter the pharmacokinetics of drugs and endogenous substances.
  • Understanding the impact of ARF on organic cation transport is vital for managing drug therapy in patients with kidney disease.

Purpose of the Study:

  • To investigate the impact of experimental kidney failure on the pharmacokinetics and tissue distribution of a model organic cation, triethylmethylammonium (TEMA).
  • To elucidate the underlying mechanisms of organic cation transporters affected by acute renal failure.
  • To determine the role of endogenous substrates in altered organic cation transport during ARF.

Main Methods:

  • Characterization of systemic pharmacokinetics and tissue distribution of TEMA in rats with and without uranyl nitrate-induced acute renal failure (UN-ARF).
  • In vitro studies using LLC-PK1 cells overexpressing rat organic cation transporter 1 (rOCT1) or rOCT2 to assess the effect of plasma from UN-ARF rats on tetraethylammonium (TEA) uptake.
  • Analysis of plasma concentration, clearance, and tissue-to-plasma concentration ratios (T/P ratio) for TEMA.

Main Results:

  • The area under the curve (AUC) for TEMA was increased in UN-ARF rats, likely due to decreased total clearance.
  • The T/P ratio of TEMA was significantly decreased in the kidneys but unchanged in the liver of UN-ARF rats.
  • In vitro, plasma from UN-ARF rats significantly decreased TEA uptake in rOCT2-overexpressing cells, but not in rOCT1-overexpressing cells, suggesting involvement of rOCT2.

Conclusions:

  • Uranyl nitrate-induced acute renal failure in rats leads to altered pharmacokinetics and kidney distribution of the organic cation TEMA.
  • The findings suggest an accumulation of endogenous organic cation substrates, likely for rOCT2, in the plasma of UN-ARF rats.
  • This accumulation of endogenous substrates may impair the transport function of rOCT2, affecting TEMA pharmacokinetics and renal distribution.

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