Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite

Abstract

Evidence that partially oxidized piperidine derivatives such as the Parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are biotransformed in a reaction catalyzed by monoamine oxidase B (MAO-B) to neurotoxic pyridinium metabolites led to studies resulting in the identification of the haloperidol-derived pyridinium metabolite in the urine of drug-treated rats. The present in vitro studies examine the metabolic pathway governing this overall four-electron oxidation. Although haloperidol and its 1,2,3,6-tetrahydropyridine dehydration product were not substrates for purified bovine liver MAO-B, both compounds were biotransformed to the pyridinium product by rat liver microsomal preparations. The dependence on NADPH and the inhibition by SKF-525A argue that one or more liver cytochrome P-450 isozymes may catalyze this transformation. Attempts to detect possible metabolic intermediates were not successful. Chemical model studies, however, suggest that the expected intermediary amino enol and dihydropyridinium species may be too unstable to isolate. The possible significance of this pathway with respect to haloperidol-induced central nervous system dysfunction is considered.

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

“…In the neuronal and lymphocyte cell lines, SH-SY5Y and U973, Heiser et al [13] reported significantly lower ATP levels after incubation with HAL. In our study, CPZ had an IC50 on ATP production lower than HAL, a finding possibly explained by the failure of endothelial cells to generate the more potent neurotoxic metabolite HPTP (1,2,3,6-tetrahydropyridine) from HAL [14].…”

Assessment of the Contributions of CYP3A4 and CYP3A5 in the Metabolism of the Antipsychotic Agent Haloperidol to Its Potentially Neurotoxic Pyridinium Metabolite and Effect of Antidepressants on the Bioactivation Pathway

“…1. These include 1) glucuronidation of the 3 0 alcohol moiety (Someya et al, 1992); 2) reduction of the carbonyl group by cytosolic carbonyl reductase, which leads to reduced HP (Eyles and Pond, 1992); 3) reverse oxidation of reduced HP back to HP (Pan et al, 1998); 4) N-dealkylation leading to the formation of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP) (Fang et al, 2001); 5) dehydration of 3 0 alcohol moiety to 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP) (Subramanyam et al, 1991a;Van der Schyf et al, 1994) , 1997). In contrast to earlier studies (Llerena et al, 1992;Viala et al, 1996) that suggested the involvement of cytochrome P450 (P450) 2D6 in HP metabolism to CPHP, HPTP, and HPP ϩ , recent reports have indicated that these pathways are almost exclusively catalyzed by CYP3A4 (Usuki et al, 1996;Fang et al, 2001).…”

“…1. These include 1) glucuronidation of the 3 0 alcohol moiety (Someya et al, 1992); 2) reduction of the carbonyl group by cytosolic carbonyl reductase, which leads to reduced HP (Eyles and Pond, 1992); 3) reverse oxidation of reduced HP back to HP (Pan et al, 1998); 4) N-dealkylation leading to the formation of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP) (Fang et al, 2001); 5) dehydration of 3 0 alcohol moiety to 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP) (Subramanyam et al, 1991a;Van der Schyf et al, 1994); 6) oxidation of the piperidin-4-ol moiety in HP to the corresponding 4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HPP ϩ ) metabolite (Usuki et al, 1996) P450, cytochrome P450; DMSO, dimethyl sulfoxide; SSRI, selective serotonin reuptake inhibitor; LC-MS/MS, high performance liquid chromatography-tandem mass spectrometry; HPLC, high performance liquid chromatography; R t , retention time; CID, collision-induced dissociation; NPP † , N-nonyl-4-phenylpyridinium. al., 1997). In contrast to earlier studies (Llerena et al, 1992;Viala et al, 1996) that suggested the involvement of cytochrome P450 (P450) 2D6 in HP metabolism to CPHP, HPTP, and HPP ϩ , recent reports have indicated that these pathways are almost exclusively catalyzed by CYP3A4 (Usuki et al, 1996;Fang et al, 2001).…”

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and 1H-NMR

“…Iminium ion formation also presumably involves oxidation at the piperidine ring ␣-carbons (Castagnoli et al, 1997). Furthermore, in certain cases (e.g., haloperidol), the N-substituted piperidines are known to undergo oxidative conversion to potentially neurotoxic pyridinium species; this conversion may also occur via a pathway that initiates with an ␣-carbon oxidation (Subramanyam et al, 1991). One possible strategy to overcome these drawbacks of the unsubstituted piperidine is the use of a 2,2,6,6-tetramethyl-piperidine moiety (2,2,6,6-TMPi 1 ) that would block the oxidation at the ␣-carbons.…”