Neurotoxic pyridinium metabolites of haloperidol, HPP and RHPP, are transported by a subset of membrane transporters

Abstract

HPP+ and RHPP+, known neurotoxic haloperidol pyridinium metabolites, has been known to distribute into the brain from systemic circulation. It is expected that various membrane transports expressed in BBB may contribute on that disposition. This study is to evaluate whether HPP+ and RHPP+ are substrates of organic cation transporters (OCTs) and P-glycoprotein (Pgp). From accumulation study of Caco-2 cells, both HPP+ and RHPP+ were accumulated with the estimated Vmax and Km of 97 pmol/ug protein/min and 4.5 μM. The intracellular concentrations of both compounds were decreased two to four fold by the pretreatment of 100 μM varapamil, 50 μM prozosin, 50 μM cimetidine, 50 μM phenoxybenzamine, and 50 μM corticosterone, which are known to have an inhibitory potential on OCTs activity. In addition, the intracellular uptake of HPP+ and RHPP+ in the OCT1 cRNA injected Xenopus oocytes were 3 folds higher than that in water injected oocytes. In the accumulation study of OCT1 and OCT2 transfected MDCK cells, over three fold higher concentrations of both metabolites were accumulated when compared to those in untransfected cells. However, there was no significant difference in the accumulation of both compounds in MDR1 overexpressed cells. These results suggest that OCTs involve in the uptake of HPP+ and RHPP+, but those seems not to be substrates of Pgp. Further study is in progress to evaluate the involvement of other membrane transporters on the disposition of both metabolites. Clinical Pharmacology & Therapeutics (2005) 77, P68–P68; doi: 10.1016/j.clpt.2004.12.151