Some aspects of the metabolism of morphine-<i>N</i>-oxide

Heimans, R. L. H.; Fennessy, M. R.; Gaff, G. A.

doi:10.1111/j.2042-7158.1971.tb10199.x

Cited by 10 publications

(3 citation statements)

References 11 publications

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“…16 For a normal isotope effect the assumption is made that the zero-point energy of a C-H and C-D bond is equal in the transition-state complex. This may not be true if (1) the transition state is nonlinear, (2) the transition state is asymmetric, or (3) the hydrogen atom involved is not undergoing translation at the saddle point.15,17 Secondly, the isotope effect on the Michaelis constants suggests that binding forces are used in the formation of the enzyme-substrate complex forcing the substrate to resemble the transition state. This results in changes in vibrational frequencies of the C-H bond to be broken in the transition state.…”

Section: Discussionmentioning

confidence: 99%

Primary and .beta.-secondary deuterium isotope effects in N-deethylation reactions

1975

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Lidocaine (1), labeled specifically with deuterium in the alpha-methylene (lidocaine-d4,2) and beta-methyl (lidocaine-d6,3) carbon atoms of the terminal amino group, was used to probe the mechanism of oxidative N-deethylation by rat liver microsomes. The reaction rates were determined by measuring the formation of acetaldehyde colorimetrically. This general assay for oxidative N-deethylation reactions has the advantages of being rapid, producing a relatively stable colored derivative and being linear over the range of 0.25-4 mug of acetaldehyde formed per milliliter of incubate. Deuterium substitution at the methylene carbon atoms, the presumed site of initial oxygen insertion, revealed a kH/kD = 1.49 +/- 0.11 and a KmD/KmH = 1.23. Deuterium substitution on the terminal methyl groups showed a kH/kD = 1.52 +/- 0.10 and a KmD/KmH = 0.92. The results are explained in terms of both primary and secondary isotope effects on a possible rate-determining step in the N-deethylation sequence.

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Section: Discussionmentioning

confidence: 99%

Primary and .beta.-secondary deuterium isotope effects in N-deethylation reactions

1975

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“…Two alternative methods were used: 1. Hydrochloric acid was added carefully to the urine to give a final concentration of 1.2 M. Bases were liberated from conjugates by autoclaving at 20 psi for 30 min (10). Ammonium hydroxide was added (to pH 10.2) and organic bases extracted with chloroformmethanol (9 : 1) (10 x 20 ml).…”

Section: In Vivo Metabolism Of Morphine and Codeinementioning

confidence: 99%

Metabolism of morphine and codeine by guinea-pig liver microsomal preparations and by rats

Phillipson

El-Dabbas

Gorrod

1978

European Journal of Drug Metabolism and Pharmacokinetics

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Incubation of morphine with guinea-pig liver microsomal preparations resulted in the formation of 0.9"1r of the major isomer of morphine N-oxide (I) whereas with codeine, 19.50/.-of the major isomer (III) and 0.10/.-of the minor isomer (IV) of codeine N-oxide were formed. Morphine -and codeine N-oxides (major isomers) were isolated in low concentrations from rat urine after administration of the corresponding tertiary alkaloids. When tacrine was given concommitantly, there were no significant increases in N-oxide formation either in vitro or in vivo. Codeine was identified as a metabolite of morphine after incubation with guinea-pig liver microsomes and after injection into rats.

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“…It has also been known for a number of years that the resultant N-oxide metabolites undergo significant reduction back to the parent compound in a number of species including rat (Bickel et al 1966, Heimans et al 1971, Dajani et al 1975), dog (McMahon and Sullivan 1977 and man (Jenner et al 1973, Powis et al 1979, Al-Waiz et al 1987. However, it is difficult to assess the relative importance in oiwo of redox processes in the metabolic disposition of these tertiary amine compounds.…”

Section: Introductionmentioning

confidence: 99%

The metabolism of chlorpromazineN-oxide in man and dog

et al. 1990

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1. The metabolism of chlorpromazine N-oxide was studied in female dogs and adult male humans after a single oral dose. 2. There was extensive metabolism in both species in that between four and seven metabolites were separately identified in urine and faeces. Apart from chlorpromazine N-oxide, chlorpromazine N,S-dioxide was the only isolated metabolite which retained the N-oxide group. The other identified metabolites were chlorpromazine and its 7-hydroxy, sulphoxide, N-desmethyl, 7-hydroxy-N-desmethyl and N-desmethylsulphoxide derivatives. 3. With dog samples, metabolites were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis. With human samples, metabolites were directly subjected to h.p.l.c.-mass spectrometric determination. With all metabolites their structures were confirmed by direct comparison of their mass spectra and chromatographic behaviours with those of authentic samples. 4. The metabolites identified in urine and faeces were for the most part the same in both species, with the exceptions that chlorpromazine N-oxide was identified in the faeces of dog only and 7-hydroxy-N-desmethylchlorpromazine was identified in the urine of man only. 5. The observation of N-oxide compounds in the excreta of both man and dog contrasted with that for the previously studied rat, where no such compounds were detected.

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Some aspects of the metabolism of morphine-N-oxide

Cited by 10 publications

References 11 publications

Primary and .beta.-secondary deuterium isotope effects in N-deethylation reactions

Primary and .beta.-secondary deuterium isotope effects in N-deethylation reactions

Metabolism of morphine and codeine by guinea-pig liver microsomal preparations and by rats

The metabolism of chlorpromazineN-oxide in man and dog

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