Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites.
Article Details
- CitationCopy to clipboard
Pekol T, Daniels JS, Labutti J, Parsons I, Nix D, Baronas E, Hsieh F, Gan LS, Miwa G
Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites.
Drug Metab Dispos. 2005 Jun;33(6):771-7. doi: 10.1124/dmd.104.002956. Epub 2005 Mar 11.
- PubMed ID
- 15764713 [ View in PubMed]
- 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 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Bortezomib Cytochrome P450 1A2 Protein Humans NoSubstrateInhibitorDetails Bortezomib Cytochrome P450 2C19 Protein Humans NoSubstrateInhibitorDetails Bortezomib Cytochrome P450 2C9 Protein Humans NoSubstrateInhibitorDetails Bortezomib Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Bortezomib Cytochrome P450 3A4 Protein Humans NoSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareBortezomibPhenobarbital The metabolism of Bortezomib can be increased when combined with Phenobarbital. BortezomibPentobarbital The metabolism of Bortezomib can be increased when combined with Pentobarbital. BortezomibPrimidone The metabolism of Bortezomib can be increased when combined with Primidone. BortezomibSt. John's Wort The metabolism of Bortezomib can be increased when combined with St. John's Wort. BortezomibRifamycin The metabolism of Bortezomib can be increased when combined with Rifamycin.