Pharmacokinetic–pharmacodynamic modeling of diltiazem in spontaneously hypertensive rats: A microdialysis study

• Published in: Journal of pharmacological and toxicological methods 2007-11, Vol.56 (3), p.290-299
• Main Authors: Bertera, Facundo M., Mayer, Marcos A., Opezzo, Javier A.W., Taira, Carlos A., Bramuglia, Guillermo F., Höcht, Christian
• Format: Article
• Language: English
• Subjects: Algorithms; Animals; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - pharmacokinetics; Area Under Curve; Blood Pressure - drug effects; Chromatography, High Pressure Liquid - methods; Chronotropic effect; Dialysis Solutions - analysis; Diltiazem; Diltiazem - administration & dosage; Diltiazem - pharmacokinetics; Dose-Response Relationship, Drug; Heart Rate - drug effects; Hypotensive effect; Injections, Intravenous; Male; Metabolic Clearance Rate; Microdialysis; Microdialysis - methods; Models, Biological; Pharmacokinetic–pharmacodynamic modeling; Plasma pharmacokinetics; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity; Spontaneously hypertensive rats
• ISSN: 1056-8719; 1873-488X
• DOI: 10.1016/j.vascn.2007.04.001

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 than the E max equation do. Chronotropic effect of 3 mg kg − 1 diltiazem was lower in SHR compared to WKY animals. Initial sensitivity ( S 0) to diltiazem chronotropic effect was greater in SHR with regards to WKY animals after administration of 1 mg kg − 1 . S 0 to diltiazem hypotensive effect was greater in SHR with regards to WKY animals after administration of both doses of diltiazem. Microdialysis sampling is a useful technique for the pharmacokinetic study and pharmacokinetic–pharmacodynamic (PK–PD) modeling of diltiazem. The modified E max model allows an accurate estimation of drug sensitivity in conditions when maximal pharmacological response can not be attained. Genetic hypertension induced changes in the pharmacokinetic and PK–PD behavior of diltiazem suggesting that SHR is an interesting animal model for pre-clinical evaluation of calcium channel blockers.