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In Vitro Pharmacokinetic Behavior of Antiviral 3-Amidinophenylalanine Derivatives in Rat, Dog and Monkey Hepatocytes.
Lányi, Katalin; Monostory, Katalin; Steinmetzer, Torsten; Jerzsele, Ákos; Pászti-Gere, Erzsébet.
Afiliación
  • Lányi K; Department of Food Hygiene, University of Veterinary Medicine, István utca 2, H-1078 Budapest, Hungary.
  • Monostory K; Research Centre for Natural Sciences, Institute of Enzymology, Magyar Tudósok 2, H-1117 Budapest, Hungary.
  • Steinmetzer T; Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, G-35032 Marburg, Germany.
  • Jerzsele Á; Department of Pharmacology and Toxicology, University of Veterinary Medicine, István utca 2, H-1078 Budapest, Hungary.
  • Pászti-Gere E; National Laboratory of Infectious Animal Diseases, Antimicrobial Resistance, Veterinary Public Health and Food Chain Safety, University of Veterinary Medicine, István utca 2, H-1078 Budapest, Hungary.
Biomedicines ; 11(3)2023 Feb 23.
Article en En | MEDLINE | ID: mdl-36979660
Type II transmembrane serine proteases represent pharmacological targets for blocking entry and spread of influenza or coronaviruses. In this study, the depletion rates of the 3-amidinophenylalanine (3-APhA)-derived matriptase/TMPRSS2 inhibitors MI-463, MI-472, MI-485 or MI-1900 were determined by LC-MS/MS measurements over a period of 300 min using suspensions of rat, dog and cynomolgus monkey primary hepatocytes. From these in vitro pharmacokinetic (PK) experiments, intrinsic clearance values (Clint) were evaluated, and in vivo pharmacokinetic parameters (hepatic clearance, hepatic extraction ratio and bioavailability) were predicted. It was found that rat hepatocytes were the most active in the metabolism of 3-APhA derivatives (Clint 31.9-37.8 mL/min/kg), whereas dog and monkey cells displayed somewhat lower clearance of these compounds (Clint 6.6-26.7 mL/min/kg). These data support elucidation of important PK properties of anti-TMPRSS2/anti-matriptase 3-APhAs using mammalian hepatocyte models and thus contribute to the optimization of lead compounds.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Biomedicines Año: 2023 Tipo del documento: Article País de afiliación: Hungria Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Biomedicines Año: 2023 Tipo del documento: Article País de afiliación: Hungria Pais de publicación: Suiza