Evaluation of Erythromycin as a Tool to Assess CYP3A Contribution of Low Clearance Compounds in a Long-Term Hepatocyte Culture.
Adult
Alprazolam
/ pharmacokinetics
Cells, Cultured
Coculture Techniques
/ methods
Cytochrome P-450 CYP3A
/ metabolism
Cytochrome P-450 CYP3A Inducers
/ pharmacology
Cytochrome P-450 CYP3A Inhibitors
/ pharmacology
Drug Evaluation, Preclinical
/ methods
Erythromycin
/ pharmacology
Female
Glucuronosyltransferase
/ metabolism
Hepatobiliary Elimination
/ drug effects
Hepatocytes
Humans
Male
Midazolam
/ pharmacokinetics
Middle Aged
Primary Cell Culture
/ methods
Rifampin
/ pharmacology
Time Factors
Journal
Drug metabolism and disposition: the biological fate of chemicals
ISSN: 1521-009X
Titre abrégé: Drug Metab Dispos
Pays: United States
ID NLM: 9421550
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
20
02
2020
accepted:
29
04
2020
pubmed:
7
6
2020
medline:
14
9
2021
entrez:
7
6
2020
Statut:
ppublish
Résumé
Long-term hepatocyte culture systems such as HepatoPac are well suited to evaluate the metabolic turnover of low clearance (CL) drugs because of their sustained metabolic capacity and longer-term viability. Erythromycin (ERY), a moderate, mechanism-based inhibitor of CYP3A, was evaluated as a tool in the HepatoPac model to assess contribution of CYP3A to the clearance of drug candidates. ERY inhibited CYP3A activity by 58% and 80% at 3 and 10 μM, respectively, for up to 72 hours. At 30 µM, ERY inhibited midazolam hydroxylation by >85% for the entire 144-hour duration of the incubation. Alprazolam CL
Identifiants
pubmed: 32503882
pii: dmd.120.090951
doi: 10.1124/dmd.120.090951
doi:
Substances chimiques
Cytochrome P-450 CYP3A Inducers
0
Cytochrome P-450 CYP3A Inhibitors
0
Erythromycin
63937KV33D
Cytochrome P-450 CYP3A
EC 1.14.14.1
Glucuronosyltransferase
EC 2.4.1.17
Midazolam
R60L0SM5BC
Rifampin
VJT6J7R4TR
Alprazolam
YU55MQ3IZY
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
690-697Informations de copyright
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.