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Eur J Clin Pharmacol. 2005 Feb;60(12):875-81. Epub 2005 Jan 19.

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

Author information

1
Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.

Abstract

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.

PMID:
15657781
DOI:
10.1007/s00228-004-0856-7
[Indexed for MEDLINE]

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