Sonia Saib1, Sophie Hodin2, Valérie Bin2, Edouard Ollier2, Xavier Delavenne2,3. 1. INSERM U1059, Dysfonction Vasculaire et Hémostase, Université Jean Monnet, 10 rue de la Marandière, Campus Santé Innovations, Saint-Priest-en-Jarez, Saint-Etienne, France. sonia.saib@univ-st-etienne.fr. 2. INSERM U1059, Dysfonction Vasculaire et Hémostase, Université Jean Monnet, 10 rue de la Marandière, Campus Santé Innovations, Saint-Priest-en-Jarez, Saint-Etienne, France. 3. Laboratoire de Pharmacologie Toxicologie Gaz du sang, CHU de Saint-Etienne, Saint-Etienne, France.
Abstract
BACKGROUND AND OBJECTIVES: 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: 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 [I1]/IC50 ratio was calculated for each combination of drugs to assess the clinical relevance of the DDIs. 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: 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.
BACKGROUND AND OBJECTIVES: 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: 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 [I1]/IC50 ratio was calculated for each combination of drugs to assess the clinical relevance of the DDIs. 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: 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.
Authors: Andre Levchenko; Bipin M Mehta; Xinle Niu; Grace Kang; Liliana Villafania; Denise Way; Dolores Polycarpe; Michel Sadelain; Steven M Larson Journal: Proc Natl Acad Sci U S A Date: 2005-01-25 Impact factor: 11.205