دورية أكاديمية
Oxidative metabolism of razuprotafib (AKB-9778), a sulfamic acid phosphatase inhibitor, in human microsomes and recombinant human CYP2C8 enzyme.
| العنوان: | Oxidative metabolism of razuprotafib (AKB-9778), a sulfamic acid phosphatase inhibitor, in human microsomes and recombinant human CYP2C8 enzyme. |
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| المؤلفون: | Camilleri P; Bio-Chemical Solutions, Stevenage, UK., Soldo B; Aerpio Pharmaceuticals, Cincinnati, OH, USA., Buch A; Aerpio Pharmaceuticals, Cincinnati, OH, USA., Janusz J; Aerpio Pharmaceuticals, Cincinnati, OH, USA. |
| المصدر: | Xenobiotica; the fate of foreign compounds in biological systems [Xenobiotica] 2021 Oct; Vol. 51 (10), pp. 1110-1121. Date of Electronic Publication: 2021 Sep 03. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Informa Healthcare Country of Publication: England NLM ID: 1306665 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1366-5928 (Electronic) Linking ISSN: 00498254 NLM ISO Abbreviation: Xenobiotica Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: London : Informa Healthcare Original Publication: London, Taylor & Francis. |
| مواضيع طبية MeSH: | Microsomes, Liver*/metabolism , Tandem Mass Spectrometry*, Acid Phosphatase/metabolism ; Aniline Compounds ; Chromatography, Liquid ; Cytochrome P-450 CYP2C8/metabolism ; Humans ; Oxidation-Reduction ; Oxidative Stress ; Sulfonic Acids |
| مستخلص: | Razuprotafib, a sulphamic acid-containing phosphatase inhibitor, is shown in vivo to undergo enzymatic oxidation and methylation to form a major metabolite in monkey and human excreta with an m/z - value of 633.LC-MS/MS analysis of samples derived from incubations of razuprotafib with human liver microsomes and recombinant CYP2C8 enzyme has elucidated the metabolic pathway for formation of the thiol precursor to the S-methyl metabolite MS633 ( m/z - 633).Under in vitro conditions, the major pathway of razuprotafib metabolism involves extensive oxidation of the thiophene and phenyl rings.A single oxidation takes place at one of the phenyl groups. Multiple oxidations occur at the thiophene moiety: initial oxidation results in the formation of a thiolactone followed by a second oxidation giving rise to an S-oxide of the thiolactone, which is further metabolised to the ring-opened form and ultimate formation of a thiol ( m/z - 619).An additional mono-oxidation pathway involves epoxidation of the thiophene followed by hydrolysis to a diol.The thiol and diol metabolites are trapped by the addition of a nucleophilic trapping agent, 3-methoxyphenacyl bromide (MPB), giving adducts with m/z - 767.The thiol is a likely precursor to the major in vivo razuprotafib metabolite, MS633. |
| فهرسة مساهمة: | Keywords: AKB-9778; CYP2C8; Razuprotafib; VE-PTP; metabolism; microsomes; sulphamic acid; thiophene |
| المشرفين على المادة: | 0 (AKB-9778) 0 (Aniline Compounds) 0 (Sulfonic Acids) EC 1.14.14.1 (CYP2C8 protein, human) EC 1.14.14.1 (Cytochrome P-450 CYP2C8) EC 3.1.3.2 (Acid Phosphatase) |
| تواريخ الأحداث: | Date Created: 20210903 Date Completed: 20211004 Latest Revision: 20211004 |
| رمز التحديث: | 20240513 |
| DOI: | 10.1080/00498254.2021.1969482 |
| PMID: | 34477046 |
| قاعدة البيانات: | MEDLINE |
PDF full text from Publisher | تدمد: | 1366-5928 |
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| DOI: | 10.1080/00498254.2021.1969482 |