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Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein


, : Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein. Bioscience Reports 36(2): -

Drug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.

US$19.90

PMID: 26823559

DOI: 10.1042/BSR20150317


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Nandakumar, M.; Karunakaran, J.; Mohanakrishnan, A.K., 2014: Diels-Alder reaction of 1,3-diarylbenzo[c]furans with thiophene S,S-dioxide/indenone derivatives: a facile preparation of substituted dibenzothiophene S,S-dioxides and fluorenones. One pot syntheses of substituted dibenzothiophene S,S-dioxides and fluorenones were successfully achieved by Diels-Alder reaction of benzo[c]furans with thiophene S,S-dioxides and indenones, respectively. Photophysical properties of representative...

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Shirlaw, J.F., 1938: On the relationship between Lahore canine fever and tick fever of dogs due to P gibsoni infection, with observations on their pathology and haemocytology. Evidence is presented that Lahore canine fever is "tick fever" (Piroplasma gibsoni infection), in a form that can only be diagnosed with extreme difficulty. The data presented are of such type that any one interested should refer to the...

Neal, T., 1980: Minimum standards aid performance. The pharmacy department at Virginia Mason Hospital developed a minimum standards document that has proved to be a valuable management tool.

Moyer, J.H.; Dennis, E.W., 1955: Treatment of hypertension. II. Pharmacology and therapy. Southern Medical Journal 48(12): 1361-76; Contd

Arzabe, C.; D.A.meida, A.C.audio C., 1997: Life history notes of Leptodactylus troglodytes in northeastern Brazil. Amphibia-Reptilia 18(2): 211-215

Roffael, E.; Dix, B.; Schneider, T., 2001: Thermomechanical (TMP) and chemo-thermomechanical pulps (CTMP) for medium density fibreboards (MDF). Thermomechanical (TMP) and chemo-thermomechanical pulps (CTMP) were prepared from spruce under different pulping conditions. The fibres were dried at 70 degrees C and medium density fibreboards (MDF) were made therefrom in pilot plant scale using...

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