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Xenobiotica
the fate of foreign compounds in biological systems
Volume 51, 2021 - Issue 10
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General Xenobiochemistry

Oxidative metabolism of razuprotafib (AKB-9778), a sulfamic acid phosphatase inhibitor, in human microsomes and recombinant human CYP2C8 enzyme

, ORCID Icon, &
Pages 1110-1121 | Received 22 Jun 2021, Accepted 11 Aug 2021, Published online: 03 Sep 2021
 

Abstract

  1. 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.

  2. 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).

  3. Under in vitro conditions, the major pathway of razuprotafib metabolism involves extensive oxidation of the thiophene and phenyl rings.

  4. 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).

  5. An additional mono-oxidation pathway involves epoxidation of the thiophene followed by hydrolysis to a diol.

  6. 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.

  7. The thiol is a likely precursor to the major in vivo razuprotafib metabolite, MS633.

Disclosure statement

No potential conflict of interest was reported by the author(s).

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