In vitro characterization of the bioconversion of pomaglumetad methionil, a novel metabotropic glutamate 2/3 receptor agonist peptide prodrug

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Richard D MoultonMichael A Mohutsky

Abstract

To characterize the hydrolysis of the peptide prodrug pomaglumetad methionil (LY2140023; (1R,4S,5S,6S)-4-(L-methionylamino)-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide), to the active drug LY404039 [(1R,4S,5S,6S)-4-amino-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide], a series of in vitro studies were performed in various matrices, including human intestinal, liver, kidney homogenate, and human plasma. The studies were performed to determine the tissue(s) and enzyme(s) responsible for the conversion of the prodrug to the active molecule. This could enable an assessment of the risk for drug interactions, an evaluation of pharmacogenomic implications, as well as the development of a Physiologically Based Pharmacokinetic (PBPK) model for formation of the active drug. Of the matrices examined, hydrolysis of pomaglumetad methionil was observed in intestinal and kidney homogenate preparations and plasma, but not in liver homogenate. Clearance values calculated after applying standard scaling factors suggest the intestine and kidney as primary sites of hydrolysis. Studies with peptidase inhibitors were performed in an attempt to identify the enzyme(s) catalyzing the conversion. Near complete inhibition ...Continue Reading

References

Jun 1, 1978·The Journal of Antibiotics·T AoyagiH Umezawa
Jan 1, 1976·The Journal of Antibiotics·H UmezawaT Takeuchi
Jun 1, 1992·The Biochemical Journal·S HowellA J Turner
Sep 21, 1988·Biochimica Et Biophysica Acta·B J CampbellW L Zahler
Dec 1, 1983·The Journal of Antimicrobial Chemotherapy·F M KahanJ Birnbaum
Mar 20, 1995·Analytical Biochemistry·S P Heywood, N M Hooper
Mar 15, 1994·The Biochemical Journal·N M HooperS Tieku
Aug 12, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·J Andrew WilliamsSimon E Ball
Apr 28, 2006·Journal of Pharmaceutical Sciences·Bianca M Liederer, Ronald T Borchardt
Dec 13, 2006·Diabetes & Vascular Disease Research : Official Journal of the International Society of Diabetes and Vascular Disease·Brian D GreenClifford J Bailey
Jun 27, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hiroyuki YamanakaTsuyoshi Yokoi
May 9, 2008·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ana L SimplícioJohn F Gilmer
Nov 12, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·S Casey LaizureZhe-Yi Hu

❮ Previous
Next ❯

Citations

Feb 5, 2019·Expert Opinion on Drug Discovery·Anas Najjar, Rafik Karaman
Jan 17, 2020·Critical Reviews in Toxicology·Patrick E Hanna, M W Anders

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.