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First published on April 19, 2006; DOI: 10.1124/dmd.105.009126

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Received for publication December 27, 2005.
Revised April 12, 2006.
Accepted for publication April 14, 2006.

Neurotoxic Pyridinium Metabolites of Haloperidol are Substrates of Human Organic Cation Transporters (hOCTs)

Ho-Jin kang 1, Sang-Seop Lee 1, Chung-Hee Lee 1, Ju-Cheol Shim 1, Ho-Jung Shin 1, Kwang-Hyeon Liu 1, Mi-Ae Yoo 1, Jae-Gook Shin 1*

1 Inje University College of Medicine

* Address correspondence to: E-mail: phshinjg{at}inje.ac.kr

Abstract

Two neurotoxic pyridinium metabolites of haloperidol, HPP+ and 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 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 appear 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.


Key words: absorption, drug transport, inhibition, neurotoxins, organic cation transport, permeability, transporters


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H.-J. Kang, I.-S. Song, H. J. Shin, W.-Y. Kim, C.-H. Lee, J.-C. Shim, H.-H. Zhou, S. S. Lee, and J.-G. Shin
Identification and Functional Characterization of Genetic Variants of Human Organic Cation Transporters in a Korean Population
Drug Metab. Dispos., April 1, 2007; 35(4): 667 - 675.
[Abstract] [Full Text] [PDF]


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