title: Interactions between bufadienolides derived from toad venom and verapamil in langendorff-perfused guinea-pig hearts.
abstract: Drug toxicity may occur due to dangerous drug combination. We aimed to investigate the influence of verapamil (a P-gp inhibitor)--bufadienolides interaction on cardiotoxicity and bufadienolide uptake by the isolated heart. The study was performed in Langendorff isolated perfused guinea-pig hearts by bufadienolides infusion in the absence and presence of verapamil (250, 500ng/ml). Arrhythmia parameters were evaluated by ECG and the content of bufadienolides in heart were measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS). In the present of verapamil, the wide QRS duration and lightly rapid heart rate (HR) were markedly reduced in the early stage of bufadienolide intoxication. However, the ECG changes characterized by prolonged P-R interval, and slow heart rate and low QRS amplitude in the late stage of bufadienolide intoxication were significantly enhanced. Furthermore, the contents of a variety of bufadienolide compounds in the verapamil+bufadienolide group were significantly higher when cardiac arrest occurred. Although verapamil reduced the bufadienolide-induced ventricular arrhythmias, verapamil worsened heart block and lethal bradycardia of bufadienolides partly via increasing the uptake of bufadienolides in heart tissue, which could compromise the protective effects of verapamil against bufadienolide intoxication. These results suggested that the verapamil may produce dangerous interactions with drugs containing bufadienolides.
authors.affiliation: Jiangsu Key Laboratory for TCM Formulae Research, Pharmacy College, Nanjing University of Chinese Medicine, No 138 Xianlin Road, Nanjing 210046, China. hongyuema@126.com
authors.forename: Hongyue
authors.initials: H
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Erxin
authors.initials: E
authors.lastname: Shang
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Lu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhan
authors.forename: Dawei
authors.initials: D
authors.lastname: Qian
authors.forename: Jinao
authors.initials: J
authors.lastname: Duan
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Fan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000664:Amphibian Venoms; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D002018:Bufanolides / Q000008:administration & dosage*; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D004347:Drug Interactions; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010477:Perfusion; D014700:Verapamil / Q000008:administration & dosage*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000664:Amphibian Venoms; D002018:Bufanolides; D002121:Calcium Channel Blockers; D014700:Verapamil