PT  - JOURNAL ARTICLE
AU  - Ho-Jin Kang
AU  - Sang-Seop Lee
AU  - Chung-Hee Lee
AU  - Ju-Cheol Shim
AU  - Ho Jung Shin
AU  - Kwang-Hyeon Liu
AU  - Mi-Ae Yoo
AU  - Jae-Gook Shin
TI  - NEUROTOXIC PYRIDINIUM METABOLITES OF HALOPERIDOL ARE SUBSTRATES OF HUMAN ORGANIC CATION TRANSPORTERS
AID  - 10.1124/dmd.105.009126
DP  - 2006 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 1145--1151
VI  - 34
IP  - 7
4099  - http://dmd.aspetjournals.org/content/34/7/1145.short
4100  - http://dmd.aspetjournals.org/content/34/7/1145.full
SO  - Drug Metab Dispos2006 Jul 01; 34
AB  - 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 Km values of 0.99, 2.79, and 2.23 μM and Vmax values of 282.1, 256.1, and 400.2 pmol/min/μg protein for hOCT1, hOCT2, and hOCT3, respectively. RHPP+ accumulated in hOCT1- and hOCT3-overexpressing MDCK cells, with estimated Km values of 5.15 and 8.21 μM and Vmax values of 1230.9 and 1348.6 pmol/min/μg 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. The American Society for Pharmacology and Experimental Therapeutics