| Autor: |
Yeste S; Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D., Reinoso RF; Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D., Ayet E; Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D., Pretel MJ; Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D., Balada A; Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D., Serafini MT; Early ADME, Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals R&D. |
| Jazyk: |
angličtina |
| Zdroj: |
Biological & pharmaceutical bulletin [Biol Pharm Bull] 2020; Vol. 43 (1), pp. 68-76. |
| DOI: |
10.1248/bpb.b19-00542 |
| Abstrakt: |
EST64454 is a selective sigma-1 receptor ligand intended for orally administered pain treatment that showed a promising profile in the lead optimization process. As part of the preliminary compound profiling, the potential for future drug-drug interactions was explored in vitro. Both direct and time-dependent CYP inhibition for CYP1A2, 2C9, 2C19, 2D6 and 3A4 was studied in human liver microsomes. EST64454 showed a low potential for CYP inhibition (IC 50 between 100 and 1000 µM) and as time-dependent inhibitor (IC 50 shift mainly around 1). CYP induction studies with HepaRG™ cells revealed no CYP induction at concentrations ≤50 µM, as shown by the CYP1A2, 3A4 and 2B6 activities measured. Reaction phenotyping was assessed after incubation with recombinant human enzymes. Although a very low metabolism was observed, several enzymes catalyzed the formation of metabolites, including CYP3A4, 2C19 and flavin monooxygenases (FMO) 1 and 3. EST64454 was not a P-glycoprotein (P-gp) substrate and was highly permeable in Caco-2 cells. P-gp inhibition was only observed at 200 µM, the highest concentration studied. Preliminary studies suggest that neither CYP nor P-gp interaction of EST64454 would be of any concern for further development. At later stages, the interaction kinetics and the clinical relevance of these findings will be thoroughly evaluated. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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