Caco-2 Permeability Studies and In Vitro hERG Liability Assessment of Tryptanthrin and Indolinone
Vorschaubild nicht verfügbar
Autor:innen
Jähne, Evelyn A.
Eigenmann, Daniela E.
Moradi-Afrapoli, Fahimeh
Butterweck, Veronika
Hebeisen, Simon
Smiesko, Martin
Hamburger, Matthias
Autor:in (Körperschaft)
Publikationsdatum
2016
Typ der Arbeit
Studiengang
Typ
01A - Beitrag in wissenschaftlicher Zeitschrift
Herausgeber:innen
Herausgeber:in (Körperschaft)
Betreuer:in
Übergeordnetes Werk
Planta Medica
Themenheft
DOI der Originalpublikation
Reihe / Serie
Reihennummer
Jahrgang / Band
82
Ausgabe / Nummer
13
Seiten / Dauer
1192-1201
Patentnummer
Verlag / Herausgebende Institution
Thieme
Verlagsort / Veranstaltungsort
Auflage
Version
Programmiersprache
Abtretungsempfänger:in
Praxispartner:in/Auftraggeber:in
Zusammenfassung
Tryptanthrin and (E,Z)-3-(4-hydroxy-3,5-dimethoxybenzylidene)indolinone (indolinone) were recently isolated from Isatis tinctoria as potent anti-inflammatory and antiallergic alkaloids, and shown to inhibit COX-2, 5-LOX catalyzed leukotriene synthesis, and mast cell degranulation at low μM to nM concns. To assess their suitability for oral administration, we screened the compds. in an in vitro intestinal permeability assay using human colonic adenocarcinoma cells. For exact quantification of the compds., validated UPLC-MS/MS methods were used. Tryptanthrin displayed high permeability (apparent permeability coeff. > 32.0 × 10-6 cm/s) across the cell monolayer. The efflux ratio below 2 (< 1.12) and unchanged apparent permeability coeff. values in the presence of the P-glycoprotein inhibitor verapamil (50 μM) indicated that tryptanthrin was not involved in P-glycoprotein interactions. For indolinone, a low recovery was found in the human colon adenocarcinoma cell assay. High-resoln. mass spectrometry pointed to extensive phase II metab. of indolinone (sulfation and glucuronidation). Possible cardiotoxic liability of the compds. was assessed in vitro by measurement of an inhibitory effect on human ether-a-go-go-related gene tail currents in stably transfected HEK 293 cells using the patch clamp technique. Low human ether-a-go-go-related gene inhibition was found for tryptanthrin (IC50 > 10 μM) and indolinone (IC50 of 24.96 μM). The anal. of compds. using various in silico methods confirmed favorable pharmacokinetic properties, as well as a slight inhibition of the human ether-a-go-go-related gene potassium channel at micromolar concns.
Schlagwörter
Pharmacology
Fachgebiet (DDC)
Veranstaltung
Startdatum der Ausstellung
Enddatum der Ausstellung
Startdatum der Konferenz
Enddatum der Konferenz
Datum der letzten Prüfung
ISBN
ISSN
1439-0221
0032-0943
0032-0943
Sprache
Englisch
Während FHNW Zugehörigkeit erstellt
Ja
Publikationsstatus
Veröffentlicht
Begutachtung
Peer-Review der ganzen Publikation
Open Access-Status
Lizenz
Zitation
JÄHNE, Evelyn A., Daniela E. EIGENMANN, Fahimeh MORADI-AFRAPOLI, Sheela VERJEE, Veronika BUTTERWECK, Simon HEBEISEN, Timm HETTICH, Götz SCHLOTTERBECK, Martin SMIESKO, Matthias HAMBURGER und Mouhssin OUFIR, 2016. Caco-2 Permeability Studies and In Vitro hERG Liability Assessment of Tryptanthrin and Indolinone. Planta Medica. 2016. Bd. 82, Nr. 13, S. 1192–1201. DOI 10.1055/s-0042-110323. Verfügbar unter: http://hdl.handle.net/11654/23406