Metabolic fate of zetidoline, a new neuroleptic agent, in man

Assandri, Alessandro; Perazzi, A; Ferrari, Pietro; Martinelli, E.; Ripamonti, A.; Tarzia, Giorgio; Tuan, G.

doi:10.1007/bf00515564

Cited by 4 publications

(4 citation statements)

References 8 publications

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“…The pyrimidine derivative, viz., 4,6 bis(pyrrolidino) pyrimidine (37), is transformed into relatively stable carbinolamine 38 upon the incubation with rat liver mi crosomes (Scheme 20). 12 One of the metabolites of 3 methylindole (39) is 3 hydroxy 3 methyloxindole (40).…”

Section: Metabolic Transformations Of Heterocyclesmentioning

confidence: 99%

“…37 The hypothetical mechanism of oxidative dearylation, 2 which is a very rare process in organic synthesis, is pre sented in Scheme 58.…”

Section: Scheme 55mentioning

confidence: 99%

“…The transformations associated with the N dearylation are more rare (see also the above mentioned data on the neu roleptic Zetidoline). 37 For example, the hepatic microso mal metabolism of N phenyl 2 naphthylamine affords the hydroxy metabolite, whose oxidation gives 2 naphtylamine and benzoquinone (Scheme 60).…”

Section: Scheme 59mentioning

confidence: 99%

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Biotransformations of drugs belonging to nitrogen heterocycles

Граник

2010

Russ Chem Bull

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The present review covers general aspects related to the metabolism of organic compounds, primarily, of biologically active azaheterocycles used as drugs. Compounds of this type occupy a dominant place among known drugs. Data on the main chemical processes determining the pathways of principal biotransformations, such as redox reactions, hydrolysis, alkylation, acy lation, various conjugations, isomerizations, and condensations, are summarized. The metabo lisms of heterocycles is considered based on the ring size of the substrate.

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Section: Metabolic Transformations Of Heterocyclesmentioning

confidence: 99%

“…37 The hypothetical mechanism of oxidative dearylation, 2 which is a very rare process in organic synthesis, is pre sented in Scheme 58.…”

Section: Scheme 55mentioning

confidence: 99%

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Biotransformations of drugs belonging to nitrogen heterocycles

Граник

2010

Russ Chem Bull

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“…N-dephenylation is not as common a metabolic pathway as N-dealkylation; however, several drugs have been reported to undergo this process either in vivo or in vitro [1][2][3][4][5][6][7][8][9][10]. Unlike N-dealkylation where P450 inserts an oxygen into the C-H bond adjacent to a nitrogen forming a carbinolamine, followed by N-C bond cleavage and leading to two products: an amine and an aldehyde or a ketone, Ndephenylation appears to occur via a N-para-hydroxy metabolite.…”

Section: Introductionmentioning

confidence: 99%

Mechanism Study of N-Dephenylation Mediated through a N-para-Hydroxy Metabolite

Wang¹,

DeMaio²,

Chandrasekaran³

et al. 2006

CDDT

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A P450 catalyzed N-para-hydroxy metabolite was suggested to be a prerequisite for N-dephenylation occurrence. Although two mechanisms have been proposed to describe this process as a consequence of either a chemical degradation or P450 lead epoxidation of the hydroxy metabolite, direct evidence has not been demonstrated. In this study, we started with a novel technique using a dipeptide, Lys-Phe, to trap the byproduct of N-dephenylation, a quinone-like compound, forming a peptide adduct to facilitate LC/MS characterization. N-dephenylation via chemical degradation was assessed by LC/MS characterization of the resulting (Lys-Phe)(2)-quinone from 4-hydroxyphenyl-2-naphthylamine following interaction with Lys-Phe in pH 7.4 buffer. N-dephenylation mediated by P450 catalysis proposed was investigated in N-para-hydroxy benzodioxane derivative incubated with mouse liver microsomes in the presence of Lys-Phe in 50/50 H(2)(16)O/H(2)(18)O. LC/MS demonstrated that only one of two hydroxy oxygens in the byproduct was exchanged with water and the MS signal intensity of the (16)O labeled peptide adduct was equal to that of (18)O labeled. These observations suggested us that the origin of the oxygen in the byproduct was from water only, not from O(2). Therefore, it appears that N-dephenylation occurs via a stepwise process, namely the substrate is initially metabolized to a N-para-hydroxy metabolite by P450, which was readily oxidized to a quinone imine/iminium chemically or enzymatically, then hydrolyzed resulting in N-dephenylation. However, in our studies, the proposed P450 mechanism involving epoxidation of a N-para-hydroxy metabolite was disproved.

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