[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 Vd/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 Vmax, dp/dtmax, LVSP, SBP and HR were about 90-120 min, showing the hysteresis loops. When using the effect compartment model, the counterclockwise hysteresis collapsed and the relationships between the effects and concentration in effect compartment were fit by using Sigmoid-Emax model. The Ce50 values of inhibitory effects on Vmax, dp/dtmax and HR of (+)-Met were 250 +/- 80, 450 +/- 210, 520 +/- 210 micrograms.L-1 and those of (-)-Met were 70 +/- 30, 70 +/- 40 and 82 +/- 27 micrograms.L-1, respectively. Significant differences of Ce50 of (+)-Met and (-)-Met were found. The values of Ce50+/Ce50- were 3.7, 6.8 and 6.3, indicating that the inhibitory effects on Vmax, dp/dtmax and HR of (-)-Met were stronger than those of (+)-Met in dogs.
Yin
X X
XX
Xuzhou Medical College, Xuzhou 221002.
Zhang
Y D
YD
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008790:Metoprolol / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D008790:Metoprolol