Effect of benzodiazepines on the metabolism of buprenorphine in human liver microsomes

Eur J Clin Pharmacol. 2005 Feb;60(12):875-81. doi: 10.1007/s00228-004-0856-7. Epub 2005 Jan 19.


Objective: To determine whether enzyme inhibition explains the clinical adverse interaction of benzodiazepines and buprenorphine.

Methods: Buprenorphine was incubated in the presence of benzodiazepines (or metabolites) with human liver microsomes (HLMs). A number of benzodiazepines were screened at therapeutic concentrations after 0-min and 15-min preincubation times. For tentative metabolically activated inhibitors, the kinetics of inhibition was studied in a secondary incubation system. Buprenorphine and norbuprenorphine were quantified by means of liquid chromatography-mass spectrometry.

Results: Buprenorphine elimination and norbuprenorphine formation were at most reduced by 26% (i.e., weak or negligible inhibition). Evidence of metabolically activated inhibition suggested the need for further studies on the inhibitory kinetics. Midazolam caused time- and concentration-dependent inhibition of norbuprenorphine formation with pseudo-first-order kinetics, and K(I) and k(inact) values of 10.5 microM and 0.045 min(-1), respectively. Mixed-type inhibition of buprenorphine elimination (K(i) = 30-35 microM) and a noncompetitive inhibition of norbuprenorphine formation were also observed. For clonazepam (up to 10 microM), 3-hydroxy-7-acetamidoclonazepam (up to 10 microM), and alpha-hydroxy-triazolam (up to 1.0 microM), no time- or concentration-dependent inhibition of buprenorphine metabolism was found.

Conclusion: A single benzodiazepine, midazolam, is a moderate mechanism-based inactivator of buprenorphine N-dealkylation. It is anticipated that repeated exposures to midazolam might alter the in vivo metabolism of buprenorphine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Opioid / metabolism*
  • Benzodiazepines / pharmacology*
  • Buprenorphine / analogs & derivatives*
  • Buprenorphine / metabolism*
  • Drug Interactions
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / metabolism*


  • Analgesics, Opioid
  • Benzodiazepines
  • Buprenorphine
  • norbuprenorphine