Pharmacokinetic-pharmacodynamic modeling of diltiazem in spontaneously hypertensive rats: a microdialysis study

Journal of Pharmacological and Toxicological Methods
Facundo M BerteraChristian Höcht

Abstract

The aim of the present work was to study the applicability of a modified E(max) pharmacodynamic model for the pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized SHR and WKY rats for simultaneous determination of unbound plasma concentrations of diltiazem and their effects on mean arterial pressure (MAP) and heart rate (HR) after the intravenous application of 1 and 3 mg kg(-1) of the drug. Correlation between diltiazem plasma levels and their cardiovascular effects was established by fitting the data to a conventional and modified E(max) model. Volume of distribution and clearance of diltiazem was greater in SHR than in WKY animals. A proportional increase of area under curve with dose increment was observed in WKY animals but not in SHR. A good correlation between plasma unbound concentrations of diltiazem and their hypotensive and chronotropic effects was found in both experimental groups using both PK-PD models. The application of the modified E(max) model for PK-PD modeling of diltiazem allowed a more accurate and precise estimation of PK-PD parameters ...Continue Reading

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Citations

Sep 10, 2013·Indian Journal of Pharmacology·Abhaya DuttaShripad B Deshpande
Jan 26, 2010·Expert Opinion on Drug Metabolism & Toxicology·Christian HöchtCarlos Alberto Taira
Oct 5, 2010·Pathophysiology : the Official Journal of the International Society for Pathophysiology·Sergei I MalekinSergei N Orlov
Nov 1, 2008·Journal of Pharmacological and Toxicological Methods·Facundo Martín BerteraChristian Höcht
Apr 30, 2008·Journal of Pharmacological and Toxicological Methods·Facundo M BerteraChristian Höcht
Aug 5, 2016·European Journal of Drug Metabolism and Pharmacokinetics·Jijie LiCairong Zhu

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