Understanding metabolism related differences in ocular efficacy of MGV354
Creators: name: Dumouchel, Jennifer L.
name: Upendra A. Argikar
name: Adams, Christopher M.
name: Prasanna, Ganesh
name: Ehara, Takeru
name: Kim, Sean
name: Breen, Chris
name: Muneto Mogi
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Physiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: 60506 Virology
subject: Computational Biology

description: <b>MGV354</b> was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. <b>MGV354</b> is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. <b>MGV354</b> has been shown to robustly lower IOP over 24 h after a single topical ocular drop in rabbit and monkey pharmacology models. However, <b>MGV354</b> failed to produce similar results in patients with ocular hypertension or open-angle glaucoma.With an objective of explaining the lack of efficacy in the clinic, we attempted to study whether human metabolism was significantly different from animal metabolism. The present study documents the investigation of metabolism of <b>MGV354</b> in an effort to understand potential differences in biotransformation pathways of <b>MGV354</b> in rabbits, monkeys, and humans.Overall twenty-six metabolites, formed via oxidative and conjugative pathways, were identified <i>in vitro</i> and <i>in vivo</i>. <i>In vitro</i> hepatic metabolism was qualitatively similar across species, with minor but distinct differences. There were no observable interspecies differences in the hepatic and ocular metabolism of <b>MGV354</b>. Although ocular metabolism was not as extensive as hepatic, the results do not explain the lack of efficacy of <b>MGV354</b> in clinical studies. <b>MGV354</b> was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. <b>MGV354</b> is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. <b>MGV354</b> has been shown to robustly lower IOP over 24 h after a single topical ocular drop in rabbit and monkey pharmacology models. However, <b>MGV354</b> failed to produce similar results in patients with ocular hypertension or open-angle glaucoma. With an objective of explaining the lack of efficacy in the clinic, we attempted to study whether human metabolism was significantly different from animal metabolism. The present study documents the investigation of metabolism of <b>MGV354</b> in an effort to understand potential differences in biotransformation pathways of <b>MGV354</b> in rabbits, monkeys, and humans. Overall twenty-six metabolites, formed via oxidative and conjugative pathways, were identified <i>in vitro</i> and <i>in vivo</i>. <i>In vitro</i> hepatic metabolism was qualitatively similar across species, with minor but distinct differences. There were no observable interspecies differences in the hepatic and ocular metabolism of <b>MGV354</b>. Although ocular metabolism was not as extensive as hepatic, the results do not explain the lack of efficacy of <b>MGV354</b> in clinical studies.