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Received for publication November 8, 2004.
Revised February 10, 2005.
Accepted for publication March 9, 2005.
Abstract Bortezomib [N-(2,3-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid] is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor that was approved in May 2003 in the United States for the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapies. Bortezomib binds the proteasome via the boronic acid moiety, and therefore, the presence of this moiety is necessary to achieve proteasome inhibition. Metabolites in plasma obtained from patients receiving a single intravenous dose of bortezomib were identified and characterized by LC/MS and LC/MS/MS. Metabolite standards that were synthesized and characterized by LC/MS/MS and high field NMR were used to confirm metabolite structures. The principal biotransformation pathway observed was oxidative deboronation, most notably to a pair of diastereomeric carbinolamide metabolites. Further metabolism of the leucine and phenylalanine moieties produced tertiary hydroxylated metabolites and a metabolite hydroxylated at the benzylic position, respectively. Conversion of the carbinolamides to the corresponding amide and carboxylic acid was also observed. Human liver microsomes adequately modeled the in vivo metabolism of bortezomib as the principal circulating metabolites were observed in vitro. Employing cDNA-expressed cytochrome P450 isoenzymes, it was determined that several isoforms contributed to the metabolism of bortezomib including CYP3A4, 2C19, 1A2, 2D6 and 2C9. The development of bortezomib has provided an opportunity to describe the metabolism of a novel boronic acid pharmacophore.
Key words:
cytochrome P450 catalyzed oxidations, drug disposition, metabolite identification
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