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First published on December 28, 2005; DOI: 10.1124/dmd.105.006148

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Received for publication June 23, 2005.
Revised November 9, 2005.
Accepted for publication December 19, 2005.

Novel metabolites of buprenorphine detected in human liver microsomes and human urine

Yan Chang 1, David E. Moody 1*, Elinore F McCance-Katz 2

1 University of Utah 2 Virginia Commonwealth University

* Address correspondence to: E-mail: dmoody{at}alanine.pharm.utah.edu

Abstract

The in vitro metabolism of buprenorphine was investigated to explore new metabolic pathways and identify the cytochrome P450s (P450s) responsible for the formation of these metabolites. The resulting metabolites were identified by liquid chromatography-electrospray ionization-tandem mass spectrometry. In addition to norbuprenorphine, two hydroxylated buprenorphine (M1 and M2) and three hydroxylated norbuprenorphine (M3, M4 and M5) metabolites were produced by human liver microsomes (HLMs), with hydroxylation occurring at the tert-butyl group (M1 and M3) and at unspecified site(s) on the ring moieties (M2, M4 and M5). Time-course and other data suggest: buprenorphine is N-dealkylated to form norbuprenorphine, followed by hydroxylation to form M3; buprenorphine is hydroxylated to form M1 and M2, followed by N-dealkylation to form M3 and M4 or M5. The involvement of selected P450s was investigated using cDNA-expressed P450s coupled with scaling models, chemical inhibition, monoclonal antibody (MAb) analysis and correlation studies. The major enzymes involved in buprenorphine elimination and norbuprenorphine and M1 formation were P450s 3A4, 3A5, 3A7, and 2C8; while 3A4, 3A5 and 3A7 produced M3 and M5. Based on MAb analysis and chemical inhibition, the contribution of 2C8 was higher in HLM with higher 2C8 activity, while 3A4/5 played a more important role in HLM with higher 3A4/5 activity. Examination of human urine from subjects taking buprenorphine showed the presence of M1 and M3; most of M1 was conjugated while 60-70% of M3 was unconjugated.


Key words: human CYP enzymes, liver microsomes, mass spectrometry, metabolite identification


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