Erythrocytic metabolism of ATLX-0199: An agent that increases minute ventilation.

Autor: Krasinkiewicz JM; Department of Pediatrics, Indiana University School of Medicine and Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA. Electronic address: krasinki@ohsu.edu., Hubbard D; Department of Pediatrics, Indiana University School of Medicine and Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA., Perez de Guzman N; Department of Pediatrics, Indiana University School of Medicine and Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA., Masters A; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Clinical Pharmacology Analytical Core, Indianapolis, IN, USA. Electronic address: argrove@iupui.edu., Zhao Y; Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: yz125@iu.edu., Gaston H; Atelerix Life Sciences, Charlottesville, VA, USA., Gaston B; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: begaston@iu.edu.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2023 Nov 05; Vol. 680, pp. 171-176. Date of Electronic Publication: 2023 Sep 15.
DOI: 10.1016/j.bbrc.2023.09.030
Abstrakt: Both L- and D-isomers of S-nitrosocysteine (CSNO) can bind to the intracellular domain of voltage-gated potassium channels in vitro. CSNO binding inhibits these channels in the carotid body, leading to increased minute ventilation in vivo. However, only the l-isomer is active in vivo because it requires the l-amino acid transporter (LAT) for transmembrane transport. In rodents and dogs, the esterified D-CSNO precursor-d-cystine dimethyl ester (ATLX-0199)-overcomes opioid- and benzodiazepine-induced respiratory depression while maintaining analgesia. Although ATLX-0199 can enter cells independently of LAT because it is an ester, its stability in plasma is limited by the presence of esterases. Here, we hypothesized that the drug could be sequestered in erythrocytes to avoid de-esterification in circulation. We developed a liquid chromatography-mass spectrometry method for detecting ATLX-0199 and characterized a new metabolite, S-nitroso-d-cysteine monomethyl ester (DNOCE), which is also a D-CSNO precursor. We found that both ATLX-0199 and DNOCE readily enter erythrocytes and neurons and remain stable over 20 min; thus ATLX-0199 can enter cells where the ester is stable, but the thiol is reduced. Depending on hemoglobin conformation, the reduced ester can be S-nitrosylated and enter carotid body neurons, where it then increases minute ventilation. These data may help explain the paradox that ATLX-0199, a dimethyl ester, can avoid de-esterification in plasma and exert its effects at the level of the carotid body.
Competing Interests: Declaration of competing interest Ben Gaston is a founder and equity holder in Atelerix Life Sciences. Herbert Gaston is an equity holder in Atelerix Life Sciences. No conflicts exist for the other authors.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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