Elimination of [14C] LY3023414 by aldehyde oxidase and CYP enzymes in humans following oral administration

Zhou, Lian; Satonin, Darlene K.; Chappell, Jill; Yi, Ping; Moulton, Richard; Callies, Sophie; Cassidy, Kenneth C.

doi:10.1016/j.dmpk.2018.09.219

Cited by 3 publications

(6 citation statements)

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“…In addition, secondary metabolites arising from sequential biotransformation steps can be accessed. In the example below, application of microbial biotransformation enabled production of the aldehyde oxidase mediated hydroxylated metabolite of samotolisib, as well as the N -oxide …”

Section: In Vitro and Surrogate Biological Systems For Biotransformationmentioning

confidence: 99%

“…Aldehyde oxidase was implicated and understood early on and found to contribute approximately half the clearance of the drug, facilitated by the production and structure elucidation of the AO-mediated hydroxylated metabolite (M2) and the N -oxide (M4) by the action of a single microbe on the parent molecule. The CYP-mediated metabolite had already been chemically synthesized separately …”

Section: In Vitro and Surrogate Biological Systems For Biotransformationmentioning

confidence: 99%

“…Provision of human CYP and non-CYP metabolites M2 (20.1 mg), M4 (66.2 mg), and M12 (18.4 mg) of Samatolisib at multi-milligram scale utilizing a mixed approach of microbial biotransformation, chemical synthesis, and liver S9 incubations …”

Section: In Vitro and Surrogate Biological Systems For Biotransformationmentioning

confidence: 99%

“…In the example below, application of microbial biotransformation enabled production of the aldehyde oxidase mediated hydroxylated metabolite of samotolisib, as well as the N-oxide. 61 Identification of AO Metabolism during Discovery: The Story of Samotolisib (LY3023414). Samotolisib (LY3023414), a dual PI3k/mTOR kinase inhibitor, was Provision of human CYP and non-CYP metabolites M2 (20.1 mg), M4 (66.2 mg), and M12 (18.4 mg) of Samatolisib at multi-milligram scale utilizing a mixed approach of microbial biotransformation, chemical synthesis, and liver S9 incubations.…”

Section: ■ Drug Design and Metabolic Stabilitymentioning

confidence: 99%

“…Samotolisib (LY3023414), a dual PI3k/mTOR kinase inhibitor, was Provision of human CYP and non-CYP metabolites M2 (20.1 mg), M4 (66.2 mg), and M12 (18.4 mg) of Samatolisib at multi-milligram scale utilizing a mixed approach of microbial biotransformation, chemical synthesis, and liver S9 incubations. 61 Figure 15. Biotransformation of ingenol disoxate to its main human metabolite (M27), using a microbial strain.…”

Section: ■ Drug Design and Metabolic Stabilitymentioning

confidence: 99%

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Biotransformation: Impact and Application of Metabolism in Drug Discovery

Shanu-Wilson

Evans

Wrigley

et al. 2020

ACS Med. Chem. Lett.

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Biotransformation has a huge impact on the efficacy and safety of drugs. Ultimately the effects of metabolism can be the lynchpin in the discovery and development cycle of a new drug. This article discusses the impact and application of biotransformation of drugs by mammalian systems, microorganisms, and recombinant enzymes, covering active and reactive metabolites, the impact of the gut microbiome on metabolism, and how insights gained from biotransformation studies can influence drug design from the combined perspectives of a CRO specializing in a range of biotransformation techniques and pharma biotransformation scientists. We include a commentary on how biology-driven approaches can complement medicinal chemistry strategies in drug optimization and the in vitro and surrogate systems available to explore and exploit biotransformation.

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Section: In Vitro and Surrogate Biological Systems For Biotransformationmentioning

confidence: 99%

Section: In Vitro and Surrogate Biological Systems For Biotransformationmentioning

confidence: 99%

Section: In Vitro and Surrogate Biological Systems For Biotransformationmentioning

confidence: 99%

Section: ■ Drug Design and Metabolic Stabilitymentioning

confidence: 99%

Section: ■ Drug Design and Metabolic Stabilitymentioning

confidence: 99%

See 3 more Smart Citations