DETECTION OF A NEUROTOXIC QUATERNARY PYRIDINIUM METABOLITE IN THE LIVER OF HALOPERIDOL-TREATED RATS

Various theories have been proposed in the past to explain the side effects associated with haloperidol treatment. In this study, we tested the hypothesis that in vivo biotransformation of haloperidol to a quaternary pyridinium metabolite might contribute to some of these effects. Administration of haloperidol (IP or by gavage) to male Wistar rats results in its biotransformation to a butyrophenone quaternary pyridinium metabolite similar to MPTP metabolism to MPP+. The corresponding methyl quaternary pyridinium compound was not detected in the liver or brain of the rats used in this study. The proposed methyl quaternary pyridinium compound and the observed butyrophenone metabolite were tested for neurotoxicity in a frog model of MPTP action and were found to have neurotoxic effects, although the methyl quaternary pyridinium compound was much more toxic.