ABSTRACT
Objective To develop a steady-state brain distribution model in rats and to assess the blood brain barrier(BBB) penetration of antipyrine, atenolol and a group of ZZB candidate compounds. Methods Antipyrine, atenolol and ZZB compounds were administered to rats by an initial iv bolus dose (loading dose) followed by iv infusion at a constant rate for 30-40 min to reach steady-state plasma kinetics. The blood and brain tissue samples were then collected. The steady-state concentrations of the samples were measured by LC-MS/MS. The steady-state ratio of brain to plasma concentration (Kp) was calculated. The drugs and candidate compounds were also tested with Caco-2 cell model and the apparent bidirectional transport permeability coefficient (Papp) was obtained. Results Antipyrine and atenolol were known as drugs with high and low BBB penetration properties respectively. The mean brain concentrations of antipyrine and atenolol at steady-state were(2561 ± 125) and(20.1±0.8)ng/g with the Kp values of 0.93 ± 0.04 and 0.015 ± 0.002, respectively. The Kp value of antipyrine was about 60 folds higher than that of atenolol. Despite the similar structures of ZZB compounds, the Kp values were varied in the range from 0.044 to 6.41. The Kp values were not correlated with Papp values yielded from Caco-2 cell model. Conclusion The established rat steady-state brain distribution model is simple, reliable and could significantly reduce the animal use. It is a practical in vivo model for assessment of BBB penetration of drugs.