RT Journal Article
SR Electronic
T1 INVESTIGATION OF DRUG-DRUG INTERACTION POTENTIAL OF BORTEZOMIB IN VIVO IN FEMALE SPRAGUE-DAWLEY RATS AND IN VITRO IN HUMAN LIVER MICROSOMES
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 702
OP 708
DO 10.1124/dmd.105.008060
VO 34
IS 4
A1 Chuang Lu
A1 Richard Gallegos
A1 Ping Li
A1 Cindy Q. Xia
A1 Sandeepraj Pusalkar
A1 Vinita Uttamsingh
A1 Darrell Nix
A1 Gerald T. Miwa
A1 Liang-Shang Gan
YR 2006
UL http://dmd.aspetjournals.org/content/34/4/702.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics