Human Metabolism of the Proteasome Inhibitor Bortezomib: Identification of Circulating Metabolites

Abstract

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.

Phase I and Pharmacokinetic Study of Bortezomib in Combination with Idarubicin and Cytarabine in Patients with Acute Myelogenous Leukemia

“…We therefore sought to define the pharmacokinetics of bortezomib when given in this regimen. Because anthracyclines are metabolized by an aldoketoreductase (34) and cytarabine by cytidine deaminase (35), their pharmacokinetics are unlikely to be altered by bortezomib (36), which is hepatically metabolized by cytochrome P450 enzymes (37,38). Therefore, the pharmacokinetic studies were limited to that of bortezomib.…”

Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib

“…(b) Furthermore, AKR1B10 could be directly involved in the detoxification of bortezomib, by carbonyl reduction of the carbonyl moiety present in this agent [N-(2,3-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid; ref. 49]. Silencing of this oxidoreductase would prolong the duration of drug exposure and thereby increase cell damage.…”

Novel Therapeutic Agents for the Management of Patients with Multiple Myeloma and Renal Impairment

“…The pharmacokinetics of bortezomib is not affected by the degree of renal impairment, and therefore dosing adjustments are not necessary for patients with renal insufficiency, including patients requiring dialysis (57). This is because the primary metabolic pathway of bortezomib, as shown in in vitro studies, is oxidative deboronation by hepatic cytochrome P450 enzymes (57)(58)(59), mainly CYP3A4, CYP2C19, and CYP1A2 (57,59,60). U.S. Food and Drug Administration (FDA) approval of the labeling regarding the use of bortezomib in patients with renal impairment was based on the findings of a U.S. National Cancer Institute-sponsored dose-escalating and pharmacologic study (61).…”