Biotransformation of [14C]-ixazomib in patients with advanced solid tumors: characterization of metabolite profiles in plasma, urine, and feces
| العنوان: | Biotransformation of [14C]-ixazomib in patients with advanced solid tumors: characterization of metabolite profiles in plasma, urine, and feces |
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| المؤلفون: | Michael J. Hanley, Cindy Q. Xia, Swapan Chowdhury, Karthik Venkatakrishnan, Sandeepraj Pusalkar, Mihaela Plesescu, Xiaoquan Zhang, Neeraj Gupta, Jing-Tao Wu |
| المصدر: | Cancer Chemotherapy and Pharmacology. 82:803-814 |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Pharmacology, Cancer Research, Metabolite, Urine, Toxicology, Tandem mass spectrometry, Ixazomib, Excretion, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Oncology, chemistry, Biotransformation, In vivo, 030220 oncology & carcinogenesis, Pharmacology (medical), Feces |
| الوصف: | This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [14C]-ixazomib. After administration of a single 4.1-mg oral dose of [14C]-ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0–168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35. TRA analysis and metabolite profiling were performed using accelerator mass spectrometry. Radiolabeled metabolites were identified using liquid chromatography/tandem mass spectrometry. Metabolite profiles were similar in plasma, urine, and feces samples across the four patients analyzed. All metabolites identified were de-boronated. In AUC0–816 h time-proportional pooled plasma, ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M3 (10.6%), and M2 (7.91%), were the primary components identified. M1 was the major metabolite, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 0–35-day postdose. As none of the identified metabolites had a boronic acid moiety, they are unlikely to be pharmacologically active. 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. |
| تدمد: | 1432-0843 0344-5704 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::83cd8661aaa3fe7553c4d003a0f34d61 https://doi.org/10.1007/s00280-018-3671-z |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........83cd8661aaa3fe7553c4d003a0f34d61 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14320843 03445704 |
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