Neurotoxic pyridinium metabolites of haloperidol are substrates of human organic cation transporters

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Ho-Jin KangJae-Gook Shin

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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Citations

Jun 10, 2014·Drug Metabolism Reviews·Jayaprakasam BolleddulaDavid L Bourdet
Jan 19, 2011·Expert Opinion on Drug Metabolism & Toxicology·Giuliano Ciarimboli
Aug 30, 2008·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·I S SongJ G Shin
Sep 3, 2008·Drug Metabolism and Pharmacokinetics·Min-Koo Choi, Im-Sook Song
Sep 5, 2013·Critical Care Nursing Quarterly·Jerry Altshuler, Brian Spoelhof
Jan 16, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ho-Jin KangJae-Gook Shin
Mar 9, 2021·Frontiers in Pharmacology·Shiwei ZhouYan Shu

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