METABOLISM OF HALOPERIDOL TO PYRIDINIUM SPECIES IN PATIENTS RECEIVINGHIGH-DOSES INTRAVENOUSLY - IS HPTP AN INTERMEDIATE

The metabolism of haloperidol (HP) to the potentially neurotoxic pyrid inium species, HPP+ and RHPP+, has been demonstrated in humans. In vit ro studies in microsomes harvested from various animal species indicat e that the tetrahydropyridines, HPTP and RHPTP, could be intermediates in this pathway. However, this has not yet been demonstrated in vivo in humans. In this study, plasma and urine collected from eight critic ally ill patients treated with high doses of intravenous HP were analy zed for HPTP and RHPTP using HPLC with electrochemical detection. Howe ver, neither HPTP nor RHPTP were detected despite plasma concentration s of HP and RHP higher than any previously reported. HPP+ and RHPP+ we re both present in the urine in high concentrations and accounted for 1.1 +/- 0.5% and 5.3 +/- 3.6%, respectively, of the administered dose of HP. The apparent elimination half-lives of HPP+ and RHPP+ were 67.3 +/- 11.0 hr and 63.3 +/- 11.6 hr, respectively. The absence of HPTP a nd RHPTP in plasma and urine suggests that in humans these tetrahydrop yridines either are insignificant intermediates in the metabolism of H P in vivo or are present only transiently at their site of formation a nd are not released into the circulation.