Diazepam metabolism

Diazepam metabolism is carried out by hepatic microsomal enzymes using an oxidative pathway of N-demethylation with the production of desmethyldiazepam, oxazepam, and to a lesser extent temazepam as metabolites.

Desmethyl diazepam is metabolized more slowly than oxazepam and is only slightly less potent than diazepam. These metabolites contribute to the sustained effect of diazepam.

The elimination half-time of diazepam metabolism is prolonged, ranging from 21 to 37 hours in healthy volunteers. Cirrhosis of the liver is accompanied by up to five fold increases in the elimination half-time of diazepam, increases progressively with increasing age, which is consistent with the increased sensitivity of these patients to the drug’s sedative effects.

The elimination half-time of diazepam metabolism is prolonged in the presence of cirrhosis of the liver and in aged population due to an increased Vd of high lipid solubility.

Compared with lorazepam, Diazepam has a longer elimination halftime but less duration of action as it dissociates more rapidly than lorazepam from GABAA receptor.

Desmethyldiazepam, the principal diazepam metabolism , has an even longer elimination half-time. Prolonged somnolence with high doses of Diazepam is likely to be due to sequestration of the parent drug and its active metabolites desmethyl diazepam in tissues, presumably fat, for subsequent release back into the circulation.

 

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