Hypnotic effects and pharmacokinetics of a single bolus dose of propofol in Japanese macaques (Macaca fsucata fsucata)

Objective To describe the hypnotic effects of a single bolus dose of propofol in Japanese macaques, and to develop a pharmacokinetic model. Study design Prospective experimental trial. Animals Four male macaques (5-6 years old, 8.0-11.2 kg). Methods The macaque was restrained and 8 mg kg−1 of propofol was administrated intravenously at 6 mg kg−1 minute−1. Behavioural changes without stimuli (first experiment) then responses to external stimuli (the second experiment) were assessed every 2 minutes for 20 minutes. Venous blood samples were collected before and at 1, 5, 15, 30, 60, 120 and 210 minutes after drug administration, and plasma concentrations of propofol were measured (third experiment). Pharmacokinetic modelling was performed using NONMEM VI. Results Macaques were recumbent without voluntary movement for a mean 14.0 ± 2.7 SD (range 10.5-16.2) or 10.0 ± 3.4 (7.2-14.5) minutes and recovered to behave as pre-administration by 25.1 ± 3.6 (22.1-30.1) or 22.2 ± 1.5 (21.1-24.3) minutes after the end of propofol administration without or with stimuli, respectively. Respiratory and heart rates were stable throughout the experiments (28-68 breaths minute−1 and 72-144 beats minute−1, respectively). Our final pharmacokinetic model included three compartments and well described the plasma concentration of propofol. The population pharmacokinetic parameters were: V1 = 10.4 L, V2=8.38 L, V3=72.7 L, CL1= 0.442 L minute−1, CL2= 1.14 L minute−1, CL3= 0.313 L minute−1, (the volumes of distribution and the clearances for the central, rapid and slow peripheral compartments, respectively). Conclusions Intravenous administration of propofol (8 mg kg−1) at 6 mg kg−1 minute−1 to Japanese macaques had a hypnotic effect lasting more than 7 minutes. A three-compartment model described propofol plasma concentrations over more than 3 hours. Clinical relevance The developed pharmacokinetic parameters may enable simulations of administration protocols to maintain adequate plasma concentration of propofol.