A COMPARATIVE-STUDY OF THE PHARMACOKINETICS OF THIOPENTAL IN THE RABBIT, SHEEP AND DOG

The central arterial pharmacokinetics of thiopental were studied in six rabbits, six sheep and six dogs after a short infusion at approximately 10 mg/kg min. Thiopental was infused to a defined electro-encephalographic endpoint (EEG burst suppression). The time to reach early burst suppression was longer in the dog (3.9 +/- 0.5 min) compared with the sheep (3.0 +/- 0.6 min) and the rabbit (2.5 +/- 0.5 min). The total dose required to produce the same level of EEG activity was higher in the dog (35.9 +/- 6.8 mg/kg) compared with the sheep (24.3 +/- 5.3 mg/kg) and the rabbit (21.6 +/- 6.8 mg/kg). The plasma concentration-time data for each animal was fitted using non-linear regression to a bi- or tri-exponential function. In all animals, the plasma-time profile was best described as a tri-exponential decay. The initial volume of distribution was similar in all three species (rabbit, 38.6 +/- 10.0 mg/kg; sheep, 44.5 +/- 9.1 ml/kg; dog, 38.1 +/- 18.4 ml/kg). The maximum arterial plasma thiopental concentration achieved at EEG burst suppression was higher in the sheep (221.8 +/- 27.9-mu-g/ml) than the dog (164.7 +/- 29.9-mu-g/ml) or the rabbit (112.3 +/- 15.1-mu-g/ml). Thiopental distribution clearance was slower in the sheep (43.6 +/- 15.1 ml/min kg) compared with the rabbit (110.5 +/- 18.7 ml/min kg) and the dog (97.2 +/- 47.2 ml/min kg). Elimination half-life was extended in the sheep (251.9 +/- 107.8 min) and dog (182.4 +/- 57.9 min) relative to the rabbit (43.1 +/- 3.4 min). The rapid half-life in the rabbit resulted from a large elimination clearance (14.6 +/- 6.8 ml/min kg) and a small steady-state volume of distribution (648.1 +/- 180.5 ml/kg). Relative to the rabbit, the other species had large steady-state volumes of distribution (dog, 815.8 +/- 119.0 ml/kg; sheep, 947.3 +/- 141.2 ml/kg), and small elimination clearances (dog, 3.4 +/- 1.0 ml/min kg; sheep, 3.0 +/- 0.9 ml/min kg). The initial disposition kinetics of thiopental in the sheep and dog were similar; however, the sheep tended to demonstrate a slower distribution clearance. The rapid and extended fall in arterial thiopental concentrations following administration in the rabbit may cause a short period of anesthesia and rapid recovery in that species. Additionally, the rabbit may require lower arterial concentrations to achieve EEG silence. The rabbit brain may be intrinsically more sensitive to barbiturates or thiopental may be capable of equilibrating with rabbit brain more rapidly than either dog or sheep brain.