Kinetics of cocaine distribution, elimination, and chronotropic effects

The pharmacokinetics of cocaine were studied in five subjects with histories of drug abuse who were otherwise healthy. A two-compartment system was used to model the distribution kinetics of the drug. The steady-state volume of distribution averaged 131.8 L or 1.96 L/kg, elimination clearance was 2.10 L/min, and the t½ was 48 minutes. Cocaine concentrations in a hypothetic biophase were estimated to correlate the chronotropic effects of this drug with its pharmacokinetics. The experimentally determined kinetic parameters indicate that the peak chronotropic effect would occur 7.3 minutes after intravenous bolus injection of cocaine, and that biophase cocaine concentrations would initially accelerate the heart rate by 0.3 bpm for each 1 ng/ml. The kinetic analysis also demonstrated that the chronotropic effects of cocaine decline more rapidly than either plasma levels or biophase concentrations. This progressive attenuation in intensity of the chronotropic effect of a given biophase cocaine concentration could be modeled as a first-order process and is compatible with either the intervention of homeostatic reflex mechanisms or the phenomenon of acute tolerance. Clinical Pharmacology and Therapeutics (1985) 38, 318–324; doi:10.1038/clpt.1985.179