Abstract
Bortezomib (Velcade, PS-341), a dipeptidyl boronic acid, is a first-in-class proteasome inhibitor approved in 2003 for the treatment of multiple myeloma. In a preclinical toxicology study, bortezomib-treated rats resulted in liver enlargement (35%). Ex vivo analyses of the liver samples showed an 18% decrease in cytochrome P450 (P450) content, a 60% increase in palmitoyl coenzyme A β-oxidation activity, and a 41 and 23% decrease in CYP3A protein expression and activity, respectively. Furthermore, liver samples of bortezomib-treated rats had little change in CYP2B and CYP4A protein levels and activities. To address the likelihood of clinical drug-drug interactions, the P450 inhibition potential of bortezomib and its major deboronated metabolites M1 and M2 and their dealkylated metabolites M3 and M4 was evaluated in human liver microsomes for the major P450 isoforms 1A2, 2C9, 2C19, 2D6, and 3A4/5. Bortezomib, M1, and M2 were found to be mild inhibitors of CYP2C19 (IC50 ∼ 18.0, 10.0, and 13.2 μM, respectively), and M1 was also a mild inhibitor of CYP2C9 (IC50 ∼ 11.5 μM). However, bortezomib, M1, M2, M3, and M4 did not inhibit other P450s (IC50 values > 30 μM). There also was no time-dependent inhibition of CYP3A4/5 by bortezomib or its major metabolites. Based on these results, no major P450-mediated clinical drug-drug interactions are anticipated for bortezomib or its major metabolites. To our knowledge, this is the first report on P450-mediated drug-drug interaction potential of proteasome inhibitors or boronic acid containing therapeutics.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.008060.
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ABBREVIATIONS: P450, cytochrome P450; CoA, coenzyme A; LC/MS/MS, liquid chromatography/tandem mass spectrometry; PBST, phosphate-buffered saline with 0.1% Tween 20.
- Received October 28, 2005.
- Accepted January 25, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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