METABOLIC INVESTIGATIONS OF THE PIPERIDINE-TYPE PHENOTHIAZINE ANTIPSYCHOTIC AGENTS WITH EMPHASIS ON THE LACTAM METABOLITES
Date
1992-06
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ORCID
Type
Degree Level
Doctoral
Abstract
Thioridazine, mesoridazine and sulforidazine are piperidine-type phenothiazine antipsychotic agents, which only differ from one another in the oxidative state of the sulfur atom at the 2-position of the phenothiazine ring. These drugs are extensively metabolized in humans and
animals. There has been no systematic investigation of the metabolites in any species although there is substantial documentation that the pathways include S-oxidations of both the phenothiazine ring and side chain sulfur atoms, aromatic hydroxylation of the phenothiazine ring followed by conjugation and N-demethylation of the piperidine ring N-substituent. There are few reports on the metabolism of the piperidine ring itself; thioridazine N-oxide is a minor
metabolite of thioridazine in rat and tentative identification has been made of the lactams of mesoridazine ring sulfoxide and sulforidazine ring suifoxide in the urine of patients. For other drugs with saturated nitrogen-containing heterocyclic ring systems, including piperidine, it is well established in various species that the metabolites include the lactams, ring opened products and N- oxides. Therefore, studies were conducted to investigate systematically the metabolic profiles in urine after oral administration of thioridazine, mesoridazine and sulforidazine in rat, dog and human, which included the definitive identification and quantification of those metabolites resultant from metabolism of the piperidine ring such as lactam and N-oxide derivatives.
Synthetic procedures were developed for the lactam analogues of thioridazine, mesoridazine and sulforidazine, their corresponding lactam ring sulfoxides, the lactam of sulforidazine ring sulfone and the N-oxide of sulforidazine. In addition, sulforidazine was synthesized and an
investigational new drug certificate was obtained that enabled its administration to human.
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Degree
Doctor of Philosophy (Ph.D.)
Department
Pharmacy