An Animal Model for Simultaneous Pharmacokinetic/Pharmacodynamic Investigations: Application to Cocaine

Abstract

An animal model suitable for pharmacokinetic/pharmacodynamic investigations is described. This model allows drug administration via different routes, serial blood sampling, serial brain ECF sampling, and monitoring the cardiovascular functions without touching the animal. This rat model was utilized to study the relationship between cocaine pharmacokinetics and the neurochemical and cardiovascular responses to cocaine administration via different routes. The pharmacokinetic results showed that the average cocaine bioavailability after i.p. administration was 71% and after oral administration was only 19.2%. Cocaine was rapidly distributed into the brain, and the brain ECF/plasma distribution ratio measured as the ratio of the brain ECF AUC to the plasma AUC was 2.02 ± 0.59. The relationship between cocaine brain ECF concentration and the change in dopamine brain ECF concentration was described by the sigmoid E_max pharmacodynamic model. When the relationship between cocaine plasma concentration and the change in the cardiovascular functions was examined, hysteresis loops were observed. These hysteresis loops may suggest the existence of an effect compartment for the cardiovascular effects of cocaine or that cocaine metabolites are contributing to cocaine cardiovascular effects. These results indicate that the described animal model is useful in simultaneous pharmacokinetic/pharmacodynamic investigations specifically for studies that involve centrally acting drugs.

Introduction

Investigations that involve simultaneous pharmacokinetic/pharmacodynamic monitoring are very important for the drug development and the drug evaluation processes. This is because these investigations are designed to describe the drug concentration–time profile in the body and characterize the relationship between this profile and the observed pharmacological activity of the drug. The design of these experiments usually involves drug administration, serial sample withdrawal, and monitoring of the drug pharmacological effects. These three major experimental activities should not interfere with one another, which makes the design of these studies very crucial for the validity and accuracy of the obtained results.

Pharmacokinetic/pharmacodynamic studies of drugs that act on the central nervous system (CNS) are complicated by the fact that drug administration and sample withdrawal may significantly affect the monitored pharmacological effects. The use of anesthetized or restrained animals is not appropriate because anesthesia and animal restraining could affect the drug pharmacological activities. Also, when a conscious freely moving animal is used, drug administration may necessitate animal handling which will have some effect on the drug pharmacological parameters at least for a certain period of time after drug administration. Furthermore, correlating the pharmacokinetic and the pharmacodynamic information obtained from different groups of animals can significantly increase the variability of the results and will make interpretation of the results more difficult.

Hutchaleelaha et al (1997)have recently addressed this problem where they reported a very useful apparatus that allowed blood sampling without interfering with monitoring of the locomotor activity. The developed apparatus was utilized in an experiment that described the relationship between cocaine pharmacokinetics and cocaine locomotor activity in rodents. The primary objective of this article is to describe an awake, freely moving animal model that is suitable for simultaneous pharmacokinetic and pharmacodynamic investigations of drugs. This model allows drug administration by different routes and serial sample withdrawal without the need to hold the animal. Also, this model allows determination of the drug brain concentration and the neurochemical response to drug administration in addition to continuous monitoring of the cardiovascular functions. This animal model was used to describe the relationship between cocaine pharmacokinetics after different routes of administration and the neurochemical and cardiovascular responses to cocaine administration.