METABOLISM OF DIAZEPAM AND RELATED BENZODIAZEPINES BY HUMAN LIVER-MICROSOMES

The metabolism of diazepam has been studied in vitro using microsomal preparations from five human livers. An HPLC method was developed for the assay of diazepam, its congeners and its metabolites. Various methods for the incorporation of diazepam into the incubation medium were explored. It was sho...

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Bibliographic Details
Published in:European journal of drug metabolism and pharmacokinetics 1992-01, Vol.17 (1), p.51-59
Main Authors: HOOPER, WD, WATT, JA, MCKINNON, GE, REILLY, PEB
Format: Article
Language:English
Subjects:
Adult
Aged
Benzodiazepines - metabolism
Biological and medical sciences
Chromatography, High Pressure Liquid
Diazepam - metabolism
Ethylmorphine-N-Demethylase - antagonists & inhibitors
Ethylmorphine-N-Demethylase - metabolism
Female
Humans
In Vitro Techniques
Life Sciences & Biomedicine
Male
Medical sciences
Microsomes, Liver - metabolism
Middle Aged
Neuropharmacology
Pharmacology & Pharmacy
Pharmacology. Drug treatments
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Science & Technology
Substrate Specificity
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Summary:The metabolism of diazepam has been studied in vitro using microsomal preparations from five human livers. An HPLC method was developed for the assay of diazepam, its congeners and its metabolites. Various methods for the incorporation of diazepam into the incubation medium were explored. It was shown that the use of organic solvents or small quantities of hydrochloric acid enhanced the solubility of this substrate. However all of the organic solvents tested were associated with substantial (around 50%) inhibition of metabolism of diazepam by both major pathways ( N-demethylation and C3-hydroxylation ). The use of hydrochloric acid gave satisfactory solubilization of diazepam, but not of pinazepam, prazepam or halazepam. Detailed metabolic studies were conducted only for diazepam, using neither hydrochloric acid nor organic solvents in the incubation medium. Formation of N-desmethyl-diazepam increased approximately linearly with diazepam concentration to 200-mu-M, and did not show saturation. Formation of temazepam gave a curved profile over the same range of diazepam concentrations, suggestive of a sigmoidal relationship. Michaelis-Menten parameters could not be determined for either reaction, but intrinsic clearances for N-demethylation varied over a 6-fold range. Diazepam N-demethylation was apparently promoted by the inclusion of temazepam in the incubation medium, while C3-hydroxylation of diazepam was enhanced in the presence of N-desmethyldiazepam. Mephenytoin in the incubation mixture had no effect on diazepam metabolism by either pathway. The present studies have defined some of the methodological problems inherent in in vitro metabolic studies with benzodiazepines, and have shed further light on the metabolism of diazepam in vitro by human liver.
ISSN:0378-7966
2107-0180
DOI:10.1007/BF03189988