Propofol in rats: testing for nonlinear pharmacokinetics and modelling acute tolerance to EEG effects

Abstract

Background and objective: Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance.

Methods: Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg⁻¹ min⁻¹. Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect.

Results: Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (V_m = 2.17 μg mL⁻¹ min⁻¹, K_m = 2.65 μg mL⁻¹, k₁₂ = 0.30 min⁻¹, k₂₁ = 0.063 min⁻¹, V_c = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid E_max model (E₀ = 17.8 Hz, E_max = 17.7 Hz, EC₅₀ = 4.1 μg mL⁻¹, γ = 2.3, k_e0 = 0.36 min⁻¹) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment.

Conclusions: For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.