Pharmacokinetic significance of luminal multidrug and toxin extrusion 1 in chronic renal failure rats

Functional and expressional depression of the rat organic cation transporter rOCT2 after 5/6 nephrectomy (Nx) is accompanied by the decreased plasma level of testosterone in the male rats. Though vectorial transport across the tubular epithelial cells is important in the secretion of cationic compounds, there has been no imformation about the luminal organic cation transporter in disease state. In the present study, the role of luminal multidrug and toxin extrusion 1 (rMATE1) was examined using female rats with or without Nx, avoiding the influence of testosterone. The tubular secretion of cimetidine was markedly decreased in female Nx rats as well as male rats. Unlike in the male rats, the plasma level of testosterone and the expression of basolateral rOCT2 were unchanged in the female rats after Nx. On the other hand, the expression of rMATE1 was markedly decreased in both male and female Nx rats, and the level of rMATE1, but not of rOCT2, correlated well with the tubular secretion of cimetidine in the female rats (r = 0.74). Immunohistochemical analysis revealed that rMATE1 and Na+/H+ exchanger (NHE) 3 were localized at the brush-border membrane of proximal tubules. The level of NHE3 was also markedly depressed in both male and female Nx rats, suggesting that the expression level on the luminal rMATE1 in combination with NHE3 was indicated to be a crucial factor for the tubular secretion of cimetidine.