Biotransformation of [14C]-ixazomib in patients with advanced solid tumors: characterization of metabolite profiles in plasma, urine, and feces

Abstract

Hydrolytic metabolism in conjunction with oxidative deboronation appears to be the principal process in the in vivo biotransformation pathways of ixazomib. The inference of formation-rate-limited clearance of ixazomib metabolites and the inferred lack of pharmacologic activity of identified circulating metabolites provides justification for use of parent drug concentrations/systemic exposure in clinical pharmacology analyses.

The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology

“…However, at higher concentrations, ixazomib was metabolized by multiple CYP isozymes with contributions by CYP3A4 > CYP1A2 > CYP2B6. 693 However, unlike bortezomib, strong inhibitors of CYP3A4 did not disturb the ixazomib metabolism. Metabolite profiles were similar in plasma, urine, and feces, and all metabolites identified were deboronated.…”

“…At clinically relevant concentrations, no single CYP450 isozymes appear to play a dominant role in its clearance. However, at higher concentrations, ixazomib was metabolized by multiple CYP isozymes with contributions by CYP3A4 > CYP1A2 > CYP2B6 . However, unlike bortezomib, strong inhibitors of CYP3A4 did not disturb the ixazomib metabolism.…”

Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism

“…Ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M2 (7.91%), M3 (10.6%) were the primary components in AUC 0–816h time-proportional pooled plasma. Hydrolytic metabolism in conjunction with oxidative de-boronation are the major metabolic pathways for ixazomib [ 47 ].…”

Metabolic profile analysis of Zhi-zi-chi decoction in feces of normal and chronic unpredictable mild stress-induced depression rats based on UHPLC-ESI-Q-TOF-MS/MS and multiple analytical strategies

“…7,[21][22][23][24] In view of the interference of a great variety of compounds and microorganisms in feces of a living organism, it is difficult to study the analytes of interest. [25][26][27] For avoiding the metabolism of the microorganisms present in the rat feces samples from affecting the composition of the sample under study, multiple analytical strategies were adopted in this study. Liquid chromatography mass spectrometry (LC-MS) has become an efficient tool for acquiring the structural information of chemical substances in biological samples due to its high separation ability and high resolution.…”