title: Interactions between verapamil and digoxin in Langendorff-perfused rat hearts: the role of inhibition of P-glycoprotein in the heart.
abstract: P-glycoprotein (P-gp) is expressed in tumour cells as well as normal tissues including heart. Modulation of P-gp transport in vivo may lead to increased drug penetrance to tissues with resulting increases in toxicity. We aimed to investigate the effects of P-gp on the isolated heart by digoxin infusion in the absence and presence of verapamil. The study was performed in Langendorff isolated perfused rat hearts. After a 20 min. stabilisation period with Tyrode Buffer, digoxin (125 μg/5 mL) was infused for 10 min. in the control group (n = 7). The same dose of digoxin was infused during perfusion with verapamil (1 nm) containing Tyrode Buffer (n = 8) in the study group. Outflow concentration and cardiac parameters of digoxin were measured at frequent intervals for 40 min. AUEC((0-40 min)) for left ventricular developed pressure was significantly increased in the presence of verapamil (4260 ± 39.37 mmHg min versus 4607 ± 98.09 mmHg min; 95% CI -587.7 to -105.8; p = 0.0083). The significant increases in left ventricular developed pressure were at 20, 25, 30, 35 and 40 min. AUC((0-40 min)) value for outflow digoxin concentration-time curve was significantly lower in the presence of verapamil. Verapamil increased the positive inotropic effect of digoxin, probably through the inhibition of P-gp, which effluxes digoxin out of cardiac cells.
authors.affiliation: Dokuz Eylul University, School of Medicine, Department of Pharmacology, Izmir, Turkey.
authors.forename: Mualla
authors.initials: M
authors.lastname: Aylin Arici
authors.forename: Emrah
authors.initials: E
authors.lastname: Kilinc
authors.forename: Omer
authors.initials: O
authors.lastname: Demir
authors.forename: Mehmet
authors.initials: M
authors.lastname: Ates
authors.forename: Alaattin
authors.initials: A
authors.lastname: Yesilyurt
authors.forename: Ayse
authors.initials: A
authors.lastname: Gelal
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004077:Digoxin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000187:drug effects; D014700:Verapamil / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin; D014700:Verapamil