Received for publication June 2, 2005.
Revised August 11, 2005.
Accepted for publication August 15, 2005.

RELATIVE CONTRIBUTIONS OF THE FIVE MAJOR HUMAN CYTOCHROMES P450, 1A2, 2C9, 2C19, 2D6, and 3A4 TO THE HEPATIC METABOLISM OF THE PROTESOME INHIBITOR BORTEZOMIB

Abstract

VELCADE^TM (bortezomib, PS-341), reversibly inhibits the 20S proteasome, and exhibits cytotoxic and antitumor activities. Pretreatment of cancer cells with bortezomib increases the chemosensitivity of these cells suggesting that bortezomib may be used in combination chemotherapy. The relative contributions of the five major human CYPs, 1A2, 2C9, 2C19, 2D6, and 3A4, the focus of the present study, to the metabolism of bortezomib are an important aspect of potential drug interactions. Relative activity factor (RAF), chemical inhibition, and immunoinhibition using monoclonal antibodies were three approaches employed to determine the relative contributions of the major human CYPs to the net hepatic metabolism of bortezomib. RAFs for the CYP isoform selective substrates were determined; the ratio of the rate of metabolism of bortezomib with cDNA-expressed CYPs versus rate of metabolism with human liver microsomes was normalized with respect to the RAF for each CYP isoform to determine the percent contributions of the CYPs to the net hepatic metabolism of bortezomib. CYP3A4 followed by CYP2C19 were determined to be the major contributors to the metabolism of bortezomib. Chemical inhibition and immunoinhibition confirmed that CYP3A4 and CYP2C19 were the major CYPs responsible for the hepatic metabolism of bortezomib. The studies were conducted with 2 µM bortezomib, and disappearance of bortezomib rather than appearance of a specific metabolite was quantified to determine the contributions of the CYPs to the overall hepatic metabolism of bortezomib in humans.

Key words: anticancer agents, cytochrome P450 isoforms, drug clearance, drug interactions, liver microsomes

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