Trantinterol, a novel β2-adrenoceptor agonist, noncompetitively inhibits P-glycoprotein function in vitro and in vivo.
P-glycoprotein (P-gp)-mediated drug-drug interactions are important factors causing adverse effects of drugs in clinical use. The aim of this study was to determine whether trantinterol (also known as SPFF), a novel β2-adrenoceptor agonist, was a P-gp inhibitor or substrate. The results showed that trantinterol was not a substrate of P-gp but increased rhodamine 123 (Rho 123) uptake by MDCK-MDR1 cells and decreased the efflux transport of both Rho 123 and cyclosporine A (CsA) in bidirectional transport studies across MDCK-MDR1 cell monolayers. This suggested that trantinterol was a P-gp inhibitor but not a P-gp substrate. The mechanism of inhibition was investigated in the P-gp-Glo assay system, where it was found that trantinterol inhibited P-gp ATPase activity in a dose-dependent manner. A subsequent study using the antibody binding assay with the conformation-sensitive P-gp-specific antibody UIC2 confirmed that trantinterol decreased UIC2 binding at 10 μM in contrast to the competitive inhibitor, verapamil. This suggested that trantinterol was a noncompetitive inhibitor of P-gp. Finally, a pharmacokinetic study in rat showed that trantinterol significantly increased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of digoxin and paclitaxel (PAC), and the Cmax of cyclosporine A (CsA). In summary, trantinterol is a potent noncompetitive P-gp inhibitor which may increase the bioavailability of other P-gp substrate drugs coadministered with it.
College of Life Science, Jilin University , Changchun, 130012, P. R. China.
Tingting
T
Wang
Yantong
Y
Sun
Wenxiao
W
Ma
Zhichao
Z
Yang
Junfeng
J
Yang
Jingrui
J
Liu
Hongbo
H
Fan
Yan
Y
Yang
Jingkai
J
Gu
John Paul
JP
Fawcett
Yingjie
Y
Guo
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000251:Adenosine Triphosphatases / Q000737:chemistry; D000318:Adrenergic beta-Agonists / Q000737:chemistry*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D019540:Area Under Curve; D001665:Binding Sites; D001692:Biological Transport; D018938:Caco-2 Cells; D002976:Clenbuterol / Q000031:analogs & derivatives* / Q000737:chemistry; D016572:Cyclosporine / Q000737:chemistry; D004077:Digoxin / Q000737:chemistry; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D017239:Paclitaxel / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000737:chemistry
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000318:Adrenergic beta-Agonists; D000911:Antibodies, Monoclonal; C542064:trantinterol; D020112:Rhodamine 123; D004077:Digoxin; D016572:Cyclosporine; D000251:Adenosine Triphosphatases; D017239:Paclitaxel; D002976:Clenbuterol
Caco-2 cells; MDCK-MDR1 cells; P-gp; noncompetitive inhibitor; trantinterol