Disposition kinetics of cocaine in rats

Abstract

Cocaine is a psychomotor stimulant which is widely abused. To understand the behavior of cocaine, the disposition kinetics of the compound were characterized using the rat as an animal model. A sensitive HPLC assay was developed to quantitate cocaine and metabolites (cocaethylene, norcocaine, benzoylecgonine, and benzoyl-norecgonine) in plasma and urine samples. Since ecgonine methyl ester has insufficient UV absorptivity, the quantitation of this compound in blood and urine was performed by a GC/NPD method. The effects of dose and route of administration on the disposition kinetics of cocaine were studied in male Sprague-Dawley rats. The total systemic clearance of cocaine following i.v. and s.c. administration are dose-independent. The clearance of cocaine (CL/F) following i.p. administration is dose-dependent. Cocaine absorption following subcutaneous injection was slow but complete (F = 1.0). The extraction ratio of cocaine in the lung (1-F) is about 0.18. The oral bioavailability of cocaine (F = 0.05) was low compared to i.p. administration (F = 0.35-0.63). Various properties of cocaine in the blood (blood clearance, blood to plasma ratio and plasma protein binding) were characterized using blood from the experimental animals and humans (male and female). Cocaine degradation in blood was dose-independent. In rat, cocaine degradation in blood was slow and due to the non-enzymatic degradation. In humans, cocaine is metabolized by a cholinesterase enzyme and this reaction can be inhibited by NaF. Ethanol had no influence on cocaine degradation either in human or rat blood. Cocaine blood to plasma ratio was dose-independent and was not influenced by NaF and ethanol. Plasma protein binding of cocaine in the rat was independent of concentration but depended upon plasma pH. Gender and time of the menstrual cycle had no influence on cocaine degradation, blood to plasma ratio or plasma protein binding in humans. A simple device has been modified for serial venous blood sampling which permits the simultaneous measurement of locomotor activity in the freely moving rat. The relationship between the locomotor activity following a single short i.v. infusion of cocaine and cocaine plasma concentrations can be adequately described by the Sigmoid-Emax model or by the same model coupled with an effect compartment.