Reduced hepatic uptake and intestinal excretion of organic cations in micewith a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene

The polyspecific organic cation transporter 1 (OCT1 [SLC22A1]) mediates fac ilitated transport of small (hydrophilic) organic cations. OCT1 is localize d at the basolateral membrane of epithelial cells in the liver, kidney, and intestine and could therefore be involved in the elimination of endogenous amines and xenobiotics via these organs. To investigate the pharmacologic and physiologic role of this transport protein, we generated Oct1 knockout (Oct1(-/-)) mice. Oct1(-/-) mice appeared to be viable, healthy, and fertil e and displayed no obvious phenotypic abnormalities. The role of Oct1 in th e pharmacology of substrate drugs was studied by comparing the distribution and excretion of the model substrate tetraethylammonium (TEA) after intrav enous administration to wild-type and Oct1(-/-) mice. In Oct1(-/-) mice, ac cumulation of TEA in liver was four to sixfold lower than in wild-type mice , whereas direct intestinal excretion of TEA was reduced about twofold. Exc retion of TEA into urine over 1 h was 53% of the dose in wild-type mice, co mpared to 80% in knockout mice, probably because in Oct1(-/-) mice less TEA accumulates in the liver and thus more is available for rapid excretion by the kidney. In addition, we found that absence of Oct1 leads to decreased liver accumulation of the anticancer drug metaiodobenzylguanidine and the n eurotoxin 1-methyl-4-phenylpyridium. In conclusion, our data show that Oct1 plays an important role in the uptake of organic cations into the liver an d in their direct excretion into the lumen of the small intestine.