In Vitro Evaluation of P-gp-Mediated Drug-Drug Interactions Using the RPTEC/TERT1 Human Renal Cell Model.
Journal
European journal of drug metabolism and pharmacokinetics
ISSN: 2107-0180
Titre abrégé: Eur J Drug Metab Pharmacokinet
Pays: France
ID NLM: 7608491
Informations de publication
Date de publication:
Mar 2022
Mar 2022
Historique:
accepted:
07
12
2021
pubmed:
23
12
2021
medline:
5
4
2022
entrez:
22
12
2021
Statut:
ppublish
Résumé
In vitro evaluation of the P-glycoprotein (P-gp) inhibitory potential is an important issue when predicting clinically relevant drug-drug interactions (DDIs). Located within all physiological barriers, including intestine, liver, and kidneys, P-gp plays a major role in the pharmacokinetics of various therapeutic classes. However, few data are available about DDIs involving renal transporters during the active tubular secretion of drugs. In this context, the present study was designed to investigate the application of the human renal cell line RPTEC/TERT1 to study drug interactions mediated by P-gp. The P-gp inhibitory potentials of a panel of drugs were first determined by measuring the intracellular accumulation of rhodamine 123 in RPTEC/TERT1 cells. Then four drugs were selected to assess the half-maximal inhibitor concentration (IC50) values by measuring the intracellular accumulation of two P-gp-substrate drugs, apixaban and rivaroxaban. Finally, according to the FDA guidelines, the [I The data showed that drugs which are known P-gp inhibitors, including cyclosporin A, ketoconazole, and verapamil, caused great increases in rhodamine 123 retention, whereas noninhibitors did not affect the intracellular accumulation of the P-gp substrate. The determined IC50 values were in accordance with the inhibition profiles observed in the rhodamine 123 accumulation assays, confirming the reliability of the RPTEC/TERT1 model. Taken together, the data demonstrate the feasibility of the application of the RPTEC/TERT1 model for evaluating the P-gp inhibitory potentials of drugs and consequently predicting renal drug interactions.
Sections du résumé
BACKGROUND AND OBJECTIVES
OBJECTIVE
In vitro evaluation of the P-glycoprotein (P-gp) inhibitory potential is an important issue when predicting clinically relevant drug-drug interactions (DDIs). Located within all physiological barriers, including intestine, liver, and kidneys, P-gp plays a major role in the pharmacokinetics of various therapeutic classes. However, few data are available about DDIs involving renal transporters during the active tubular secretion of drugs. In this context, the present study was designed to investigate the application of the human renal cell line RPTEC/TERT1 to study drug interactions mediated by P-gp.
METHODS
METHODS
The P-gp inhibitory potentials of a panel of drugs were first determined by measuring the intracellular accumulation of rhodamine 123 in RPTEC/TERT1 cells. Then four drugs were selected to assess the half-maximal inhibitor concentration (IC50) values by measuring the intracellular accumulation of two P-gp-substrate drugs, apixaban and rivaroxaban. Finally, according to the FDA guidelines, the [I
RESULTS
RESULTS
The data showed that drugs which are known P-gp inhibitors, including cyclosporin A, ketoconazole, and verapamil, caused great increases in rhodamine 123 retention, whereas noninhibitors did not affect the intracellular accumulation of the P-gp substrate. The determined IC50 values were in accordance with the inhibition profiles observed in the rhodamine 123 accumulation assays, confirming the reliability of the RPTEC/TERT1 model.
CONCLUSIONS
CONCLUSIONS
Taken together, the data demonstrate the feasibility of the application of the RPTEC/TERT1 model for evaluating the P-gp inhibitory potentials of drugs and consequently predicting renal drug interactions.
Identifiants
pubmed: 34935100
doi: 10.1007/s13318-021-00744-7
pii: 10.1007/s13318-021-00744-7
doi:
Substances chimiques
Rivaroxaban
9NDF7JZ4M3
Ketoconazole
R9400W927I
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
223-233Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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