CONCENTRATION-TIME PROFILES OF AMLODIPINE, GLYBURIDE, AND DIGOXIN IN RATS: PREDICTIONS USING A CONTINUOUS ABSORPTION MODEL

Abstract

The most common route of administration is oral, despite absorption barriers leading to variable exposure and therapeutic effect. Preclinical species are used to study this variability, though they are expensive and time-consuming. Modeling and simulation provide an alternative to preclinical studies. In this study, a continuous rodent absorption model was developed and refined to predict drug absorption prior to entering animals. The continuous absorption model describes the change in drug concentration over distance and time. The intestine is defined by a physiologically based pharmacokinetic (PBPK) model, which is attached to a simpler classical compartmental model to represent the rest of the body. Physiological factors and drug physicochemical properties will be incorporated to predict the absorption profiles of amlodipine (AML), glyburide (GLY), and digoxin (DIG). The anatomy of the gastrointestinal tract and therefore, the physiological factors inputted into the model, are species specific. The region lengths, such as the jejunum, and absorptive surface area amplifiers, such as the villi, of the small intestine differ in humans versus rats. In addition, the stomach composition and presence of the gallbladder is not consistent between the two species. Similarly, food alters the physiology of the intestines. Periods of fasting can induce changes in intestinal pH and gastrointestinal motility. Chapter One details the background concerning this project, along with the hypothesis and goals. Chapter Two involves the development and validation for bioanalytical methods for the drugs of interest. Chapter Three discusses the collection of anatomical data, specifically the intestinal pH and gastrointestinal motility under fed and fasted conditions. Chapter Four includes in vitro ADME data collection and in vivo IV pharmacokinetic studies in male Sprague-Dawley rats to determine the systemic disposition functions in for amlodipine (AML), glyburide (GLY) and digoxin (DIG). Chapter Five includes the in vivo pharmacokinetic studies in male Sprague-Dawley rats to determine the effect of food on the absorption of amlodipine (AML), glyburide (GLY) and digoxin (DIG). Chapter Six details the in vivo rat studies involving the influence of particle size on GLY suspension absorption. Chapter Seven discusses the input of physiological factors and prediction of drug absorption using a continuous absorption model in rats. Chapter Eight details future directions and the summary of the project.