In vitro ADME, mouse pharmacokinetics of LD14b, and bioanalysis of a novel aß 17ß-HSD10 modulator for the treatment of Alzheimer's disease.
Xenobiotica
; : 1-12, 2024 Sep 16.
Article
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| MEDLINE
| ID: mdl-39282717
ABSTRACT
LD14b is an amyloid-ß (Aß) 17ß-hydroxysteroid dehydrogenase type 10 (Aß-17ß-HSD10) protein-protein interaction modulator that shows promising in vitro and ex vivo activity to rescue Aß-induced mitochondrial dysfunction, Aß-induced toxicity, and Aß-mediated inhibition of estradiol synthesis.The current study investigated in vitro human S9 fractions metabolic stability, apparent permeability, human and mouse plasma protein binding, in vivo pharmacokinetics, and tissue distribution in Balb/cJ mice. A fast (8-min), sensitive, reliable, and reproducible LC-MS/MS method was developed and validated over the dynamic range of 1-1000 ng/mL for the quantification of LD14b in different biological matrices (plasma, liver, kidney, brain, lungs, heart).LD14b was metabolically stable in human liver S9 fractions with 70% remaining after 90 minutes of incubation, showed intermediate apparent permeability of 3.55 × 10-06 cm/s and 6.16 × 10-06 cm/s for apical-to-basolateral (A-to-B) and basolateral-to-apical (B-to-A), respectively across the Caco-2 monolayer, and was medium/highly bound to human plasma proteins (84.1%), mouse plasma proteins (85.7%), and mouse brain homogenate (95.4%).LD14b showed an in vivo predicted % absorption of 52% in Balb/cJ mice and was well-distributed to the peripheral tissues (liver, kidney, lungs, and heart) including the brain.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Xenobiotica
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido