Abstract
Two neurotoxic pyridinium metabolites of haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxybutyl]pyridinium ion (HPP(+)) and 4-(4-(chlorophenyl)-1-4-(fluorophenyl)-4-hydroxybutyl-pyridinium (RHPP(+)), are formed in the liver and found in the brain. To understand how these neurotoxic pyridinium metabolites are distributed in the brain, HPP(+) and RHPP(+) were evaluated as substrates for human organic cation transporters (hOCTs). Both HPP(+) and RHPP(+) were accumulated in Caco-2 cells, and these accumulations were significantly inhibited by pretreatment with the hOCT inhibitors verapamil, cimetidine, phenoxybenzamine, and corticosterone. The contribution of each hOCT was evaluated based on measurements of the intracellular concentrations of haloperidol metabolites in Madin Darby canine kidney (MDCK) cells transfected with hOCT1, hOCT2, or hOCT3. HPP(+) accumulated in hOCT-overexpressing MDCK cells in a concentration-dependent manner, with estimated K(m) values of 0.99, 2.79, and 2.23 microM and V(max) values of 282.1, 256.1, and 400.2 pmol/min/microg protein for hOCT1, hOCT2, and hOCT3, respectively. RHPP(+) accumulated in hOCT1- and hOCT3-overexpressing MDCK cells, with estimated K(m) values of 5.15 and 8.21 microM and...Continue Reading
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