title: Neurotoxic pyridinium metabolites of haloperidol are substrates of human organic cation transporters.
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 V(max) values of 1230.9 and 1348.6 pmol/min/microg protein for hOCT1 and hOCT3, respectively. On the other hand, RHPP(+) did not accumulate in the hOCT2-expressing MDCK cells. These results suggest that HPP(+) and RHPP(+) are substrates for hOCTs, with the exception of RHPP(+) for hOCT2. Thus, hOCTs seem to contribute to the disposition of these toxic metabolites in human subjects, although further in vivo studies are required to elucidate the involvement of hOCTs in the disposition of haloperidol pyridinium metabolites.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea.
authors.forename: Ho-Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Sang-Seop
authors.initials: SS
authors.lastname: Lee
authors.forename: Chung-Hee
authors.initials: CH
authors.lastname: Lee
authors.forename: Ju-Cheol
authors.initials: JC
authors.lastname: Shim
authors.forename: Ho Jung
authors.initials: HJ
authors.lastname: Shin
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Yoo
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000633:toxicity; D018938:Caco-2 Cells; D002927:Cimetidine / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D010643:Phenoxybenzamine / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000378:metabolism* / Q000633:toxicity; D014162:Transfection; D000099254:Organic Cation Transporter 3
chemical_list: D014150:Antipsychotic Agents; D002927:Cimetidine; D003345:Corticosterone; D006220:Haloperidol; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D010643:Phenoxybenzamine; D011726:Pyridinium Compounds; D000099254:Organic Cation Transporter 3; C090439:4-(4-chlorophenyl)-1-(4-(4-fluoro-phenyl))-4-hydroxybutylpyridinium; C491013:SLC22A2 protein, human