HALOPERIDOL AND ITS TETRAHYDROPYRIDINE DERIVATIVE (HPTP) ARE METABOLIZED TO POTENTIALLY NEUROTOXIC PYRIDINIUM SPECIES IN THE BABOON

The in vivo metabolic fate of haloperidol (HP) and its tetrahydropyrid ine analog HPTP have been examined in the baboon to investigate the fo rmation of potentially neurotoxic pyridinium metabolites that have bee n observed previously in humans. Urine samples collected from baboons treated with HPTP were shown to contain, in addition to the parent dru g, the corresponding reduced HPTP (RHPTP), generated by reduction of t he butyrophenone carbonyl group. RHPTP was characterized by comparison with a synthetic standard using HPLC with electrochemical detection a nd HPLC/MS/MS. Another compound identified by LC/MS/MS was a glucuroni de metabolite of RHPTP. The HP pyridinium (HPP+) and reduced pyridiniu m (RHPP(+)) metabolites were shown to be present in urine from both HP and HPTP treated baboons by HPLC using fluorescence detection. The ur inary excretion profile of HPP+ and RHPP(+) in both groups was essenti ally identical and, in contrast to that observed in rodents, closely p aralleled the profile found in humans treated with HP. These data in t he baboon suggest that the metabolic processes involved in the product ion of the pyridinium metabolites of HP are similar to those in humans . Furthermore, the HPTP-treated baboon may be an appropriate model in which to study the role of pyridinium metabolites in the induction of tardive dyskinesia.