Application of radiotelemetry in pharmacokinetic-pharmacodynamic modeling of procainamide and N-acetylprocainamide in sedentary and exercise trained rats

Abstract

Understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of a new drug in an appropriate animal model provides a scientific framework for efficient and rational drug development. Cardiovascular measurements from small animals are difficult or impossible to obtain. The conventional methods, chemical restraint, physical restraint, cuff blood pressure and tethering used to obtain cardiovascular PD have limitations. These methods affect physiological function of animals and introduce stress artifact into data. Recently, radiotelemetry has been proposed as a new method to obtain cardiovascular PD from small animals. The objective of this research was to investigate the application of radiotelemetry in the pharmacokinetic/pharmacodynamic (PK/PD) modeling of cardiovascular agents in small animals. PD of various cardioactive agents such as procainamide (PA) and its active metabolite, N-acetylaprocainamide (NAPA) were evaluated. Additionally, one of the objectives of this dissertation was to evaluate the effects of exercise training on the pharmacokinetics of a model substrate of N-acetylation reactions (phase II enzymes). PA was chosen as a model drug for these studies. Radiotelemetry avoided the stress associated with animal handling and the use of anesthesia during PD studies, which allowed for the attainment of higher quality and more accurate data. PA displayed a significant increase in QT, QR and QS intervals from the baseline. The QT prolongation has been used as a surrogate marker in PA clinical studies. The PK of PA and NAPA were best described by a one compartment model. An Emax model was able to accurately describe the relationship between PA concentration and the QT interval. Effects of exercise training on the PK as well as PD of PA and NAPA were evaluated using radiotelemetry. Rats were exercised for four weeks by treadmill running. These studies noted that four weeks of exercise training did not alter the PK or PD of PA and NAPA suggesting that exercise training may not have significantly affected N-acetyltransferase. In conclusion, radiotelemetry allows the prediction of the PK/PD relationship observed in clinical studies by conducting such studies in small animals.