PHARMACOKINETIC PHARMACODYNAMIC MODELING OF METOPROLOL ENANTIOMERS IN THE DOG

The PK-PD model of (+)-Met and (-)-Met was studied in anesthetized dogs. The plasma drug concentration-time profiles were most adequately described by two compartment model. Significant differences of V_d/F, CLs/F and AUC between (+)-Met and (-)-Met were observed. The peak times of plasma (+)-Met and (-)-Met concentration in dogs were 24±5 and 30±5 min, respectively. But the peak times of drug inhibitory effects on V_max, dp/dt_max, LVSP, SBP and HR were about 90～120 min, showing the hysteresis loops. When using the effect compartment model, the counterclock-wise hysteresis collapsed and the relationships between the effects and concentration in effect compartment were fit by using Sigmoid-E_max model. The Ce₅₀ velues of inhibitory effects on V_max, dp/dt_max and HR of (+)-Met were 250±80, 450±210, 520±210 μg·L^-1 and those of (-)-Met were 70±30, 70±40 and 82±27 μg·L^-1, respectively. Significant differences of Ce₅₀ of (+)-Met and (-)-Met were found. The values of Ce₅₀₊/Ce_50- were 3.7, 6.8 and 6.3, indicating that the inhibitory effects on V_max, dp/dt_max and HR of (-)-Met were stronger than those of (+)-Met in dogs.