当前位置： SCI文献检索 > JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS期刊下所有文献 > Monophasic action potential in anaesthetized guinea pigs as a biomarker for prediction of liability for drug-induced delayed ventricular repolarization.

Monophasic action potential in anaesthetized guinea pigs as a biomarker for prediction of liability for drug-induced delayed ventricular repolarization.

Abstract：

INTRODUCTION:Drug-induced QT interval prolongation has been one of the critical issues for developing new chemical entities and pharmaceutical companies need to evaluate the risk early in the development stage. At such stage, guinea pigs are appropriate due to their small size requiring only small amounts of test drugs. The purpose of this study was to determine the utility of guinea pig monophasic action potential (MAP) using 12 reference drugs in order to clarify prediction of the QT interval prolonging risk. METHODS:Male guinea pigs were anaesthetized with pentobarbital (40 mg/kg, i.p.). Parameters analyzed were epicardial MAP duration (MAP(90)) at sinus rhythm (MAP(90(sinus))) and MAP(90) during atrial pacing (MAP(90(pacing))). Test drugs were administered to animals intravenously and cumulatively. RESULTS:Vehicle control did not affect the parameters tested. All 8 QT-prolonging drugs prolonged MAP(90(sinus)) and MAP(90(pacing)) dose-dependently, whereas all 4 non-QT-prolonging drugs showed no or very slight prolongations of these MAP(90) parameters. Rank order potency of MAP(90(pacing)) prolongations by the QT-prolonging drugs tended to correspond to clinical plasma concentrations associated with QT interval prolongations or Torsades de Pointes but showed less of a link with hERG inhibition activities. CONCLUSION:The present study demonstrates that the MAP model using anaesthetized guinea pigs could predict the liability of drugs for QT interval prolongation with high accuracy. QT assessment using the combination of the hERG assay with high sensitivity and the current in vivo assay would be desirable for early risk assessment within drug development.

journal_name

J Pharmacol Toxicol Methods

journal_title

Journal of pharmacological and toxicological methods

authors

Tabo M,Kimura K,Ito S

doi

10.1016/j.vascn.2006.11.002

subject

Has Abstract

pub_date

2007-05-01 00:00:00

pages

254-61

issue

eissn

1056-8719

issn

1873-488X

pii

S1056-8719(06)00124-9

journal_volume

pub_type

杂志文章

在线工具

Monophasic action potential in anaesthetized guinea pigs as a biomarker for prediction of liability for drug-induced delayed ventricular repolarization.