In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Abstract

ABSTRACT:The neurotoxic side effects observed for the neuroleptic agent haloperidol have been associated with its pyridinium metabolite. In a previous study, a silicon analog of haloperidol (sila-haloperidol) was synthesized, which contains a silicon atom instead of the carbon atom in the 4-position of the piperidine ring. In the present study, the phase I metabolism of sila-haloperidol and haloperidol was studied in rat and human liver microsomes. The phase II metabolism was studied in rat, dog, and human hepatocytes and also in liver microsomes supplemented with UDP-glucuronic acid (UDPGA). A major metabolite of haloperidol, the pyridinium metabolite, was not formed in the microsomal incubations with silahaloperidol. For sila-haloperidol, three metabolites originating from opening of the piperidine ring were observed, a mechanism that has not been observed for haloperidol. One of the significant phase II metabolites of haloperidol was the glucuronide of the hydroxy group bound to the piperidine ring. For sila-haloperidol, the analogous metabolite was not observed in the hepatocytes or in the liver microsomal incubations containing UDPGA. If silanol (SiOH) groups are not glucuronidated, introducing silanol groups in drug molecules could provide an opportunity to enhance the hydrophilicity without allowing for direct phase II metabolism. To provide further support for the observed differences in metabolic pathways between haloperidol and sila-haloperidol, the metabolism of another pair of C/Si analogs was studied, namely, trifluperidol and sila-trifluperidol. These studies showed the same differences in metabolic pathways as between sila-haloperidol and haloperidol.Haloperidol was developed in the late 1950s and was found to be a potent neuroleptic agent (Janssen et al., 1959). Haloperidol is a dopamine (D 2 ) receptor antagonist and is still used in the treatment of schizophrenia, although it may cause severe extrapyramidal side effects, including parkinsonism and tardive dyskinesia (Levinson, 1991;Casey, 1995). The pyridinium metabolite of haloperidol has been proposed to contribute to these neurotoxic side effects because it structurally resembles 1-methyl-4-phenylpyridinium (commonly referred to as MMP ϩ ), an inducer of Parkinson disease-like symptoms (Subramanyam et al., 1991a;Dauer and Przedborski, 2003).In the search for analogs of haloperidol, a silicon analog (silahaloperidol) was synthesized, where the quaternary R 3 COH carbon atom in the piperidine ring was replaced by a silicon atom (R 3 SiOH). The synthesis and the physicochemical and pharmacological properties of sila-haloperidol have been reported previously (Tacke et al., 2004a(Tacke et al., , 2008. As a minor part of an extensive study of sila-haloperidol, including synthesis and pharmacological properties, three major phase I metabolites in human liver microsomes (HLMs) were tentatively identified. One of these metabolites was proposed to be formed via N-dealkylation and the other two by opening of the piperidine ring (Tacke et al., 2008). Th...

Electrochemistry-mass spectrometry to study reactive drug metabolites and CYP450 simulations

“…Authors have observed the pyridinium ion by both electrochemical oxidation and incubation in the presence of rat-liver microsomes. This cutting-edge approach using EC-MS led to the elimination of the pyridinium-ion metabolite by modifying the pyridinium ring with a silica atom [46]. In addition, they reported the use of the cyanide ion as a chemical-trapping agent of the carbocationic intermediate [16].…”

The Influence of Bioisosteres in Drug Design: Tactical Applications to Address Developability Problems

“…Indeed, the metabolism of sila-haloperidol ( 220 ) follows more conventional pathways associated with the piperidine moiety in which oxidative metabolism occurs adjacent to the N atom leading to dealkylation of the fluorophenyl-containing side chain to afford 225 and ring hydroxylation that produces 228 and 230 (Fig. 34 ) [ 334 ].

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B(C6F5)3‐Catalyzed sp3 C—Si Bond Forming Consecutive Reactions

“…Silicon‐linked heterocycles have long been recognized as carbon isosteres of numerous bioactive molecules since silicon has unique physicochemical properties . Considering the abundance of N ‐heterocyclic units embedded in pharmacophores and alkaloids, the synthesis of sila‐ N ‐heterocycles is of special interest in a broad areas of chemistry . While there were no catalytic procedures documented for synthesis of such azasilaheterocycles, Park and Chang group recently conceived a new transformation of N ‐aryl piperidines leading to polycyclic sila‐ N ‐heterocycles via cascade processes involving consecutive dehydrogenation, hydrosilylation, and dehydrogenative coupling with the N ‐tolyl C(sp 2 )—H bond mediated by a single catalyst B(C 6 F 5 ) 3 .…”