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

  • E. Maria Savenije-Chapel
  • Aalt Bast
  • Jan Noordhoek
Original Papers

Summary

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 × 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.

Key-words

Diazepam product inhibition perfused liver cytochrome P-450 

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Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • E. Maria Savenije-Chapel
    • 1
  • Aalt Bast
    • 2
  • Jan Noordhoek
    • 1
  1. 1.Department of Pharmacology and Pharmacotherapy, Faculty of PharmacyState University of UtrechtUtrechtThe Netherlands
  2. 2.Department of PharmacochemistryFree University, Subfaculty ChemistryAmsterdamThe Netherlands

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