The effects of P-glycoprotein inhibition on digoxin pharmacodynamics in isolated rat hearts


Arıcı M. A., Kılınç M. E., Demir Ö., Ateş M., Gelal A.

BASIC AND CLINICAL PHARMACOLOGY AND TOXICOLOGY, vol.1, no.105, pp.73, 2009 (SCI-Expanded)

Abstract

THE EFFECTS OF P-GLYCOPROTEIN INHIBITION ONDIGOXIN PHARMACODYNAMICS IN ISOLATED RATHEARTSArici A.1,KilincE.2,DemirO.1,AtesM.3, Gelal A.11Department of Pharmacology, Faculty of Medicine, Dokuz Eylul Uni-versity, Izmir, Turkey;2Department of Analytical Chemistry, Ege Univer-sity Pharmacy Faculty, Izmir, Turkey;3Advanced Professional School ofHealth Sciences, Faculty of Medicine, Dokuz Eylul University, Izmir,TurkeyIntroduction:P-glycoprotein (P-gp) is expressed in tumor cells as wellas normal tissues including heart. In some cases of atrial fibrilationdigoxin which is a P-gp substrate is used in combination with verapamil.Clinical experience suggests that verapamil may increase digoxin toxicitythrough inhibition of P-gp activity resulting in a decreased renal elimina-tion. We aimed to investigate the effects of P-gp on the isolated heart bydigoxin infusion in the absence and presence of verapamil.Materials and Methods:The study was performed in Langendorff iso-lated perfused rat hearts. After 20 min stabilization period with Tyrodebuffer, digoxin (25lg) was infused for 10 min in control group (n = 8).Same dose digoxin was infused during perfusion with verapamil (1 nM)containing Tyrode buffer (n = 8) in the study group. Coronary perfusionpressure (CPP), Left Ventricular Developed Pressure (LVDP), maximumrates of LVP development (dp/dtmax) and Heart Rate (HR) were recordedfor 40 min. The area under effect curve during the first 40 min (AUEC0–40 min) was calculated by linear trapezoidal method.Results:AUEC0-40 minfor LVDP was significantly increased by verap-amil (4260 ± 39.37 vs. 4607 ± 98.09; %95 CI -587.7 to -105.8;P = 0.0083). The significant increases in LVDP were at 20, 25, 30, 35and 40 min. However, the increase in the dp/dtmaxwas only significantat 40 min.Conclusion:The enhancement of LVDP in the rat hearts perfused byverapamil could be due to decrease in P-gp mediated efflux of digoxin.