Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites.
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 therapy. 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 liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Metabolite standards that were synthesized and characterized by LC/MS/MS and high field nuclear magnetic resonance spectroscopy (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. Using cDNA-expressed cytochrome P450 isoenzymes, it was determined that several isoforms contributed to the metabolism of bortezomib, including CYP3A4, CYP2C19, CYP1A2, CYP2D6, and CYP2C9. The development of bortezomib has provided an opportunity to describe the metabolism of a novel boronic acid pharmacophore.
Pekol
Teresa
T
Department of Drug Metabolism and Pharmacokinetics, Drug Safety and Disposition, Millennium Pharmaceuticals Inc., 45 Sidney St., Cambridge, MA 02139, USA.
Daniels
J Scott
JS
Labutti
Jason
J
Parsons
Ian
I
Nix
Darrell
D
Baronas
Elizabeth
E
Hsieh
Frank
F
Gan
Liang-Shang
LS
Miwa
Gerald
G
D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology*; D000069286:Bortezomib; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*
D001897:Boronic Acids; D007527:Isoenzymes; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex