Inhibition of diazepam metabolism in microsomal- and perfused liver preparations of the rat by desmethyldiazepam, N-methyloxazepam and oxazepam

Eur J Drug Metab Pharmacokinet. Jan-Mar 1985;10(1):15-20. doi: 10.1007/BF03189692.

Abstract

Hydroxylated metabolites of diazepam can be conjugated and are therefore generally thought not to affect the metabolism of diazepam. Liver microsomes, obtained from phenobarbital-pretreated rats, showed an inhibition of diazepam (10(-5) M) metabolism by desmethyldiazepam as well as by N-methyloxazepam or oxazepam (5 X 10(-5) M). In a single-pass perfusion of the rat liver an inhibition of diazepam disposition by exogenously administered desmethyldiazepam and by hydroxylated diazepam metabolites was also demonstrated. No oxazepam glucuronides were found after oxazepam infusion. However, infusion with N-methyloxazepam resulted in large amounts of oxazepam-glucuronides. The results indicate that administration of N-demethylated as well as hydroxylated metabolites may result in inhibition of the metabolism of their precursor. If hydroxylated metabolites are formed in situ they become more easily conjugated in comparison with administered hydroxylated metabolites and are therefore less effective as inhibitor.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Bile / metabolism
  • Diazepam / analogs & derivatives*
  • Diazepam / metabolism*
  • Hydroxylation
  • In Vitro Techniques
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism*
  • Nordazepam / pharmacology*
  • Oxazepam / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Temazepam / pharmacology*

Substances

  • Anti-Anxiety Agents
  • Nordazepam
  • Oxazepam
  • Temazepam
  • Diazepam