普萘洛尔及4-羟普萘洛尔的药效动力学分析

PHARMACODYNAMIC ANALYSIS OF PROPRANOLOL AND 4-HYDROXYPROPRANOLOL

本文在20名健康志愿者中探讨了普萘洛尔(PPL)及活性代谢物4-羟普萘洛尔(4—OH—P)的药效学特征,建立了普萘洛尔的药代—药效学(PK—PD)统一模型。口服普萘洛尔后,普萘洛尔血药浓度与静息时心率和血压抑制效应相关性较差,而与运动时抑制效应相关性较好;4-羟普萘洛尔不仅本身浓度与负性频率效应有良好相关性,而且还能显著提高PPL的量效关系,显示4-羟普萘洛尔在普萘洛尔的β阻滞效应中发挥着重要作用。多次给药后普萘洛尔的AUC比单次给药增加1.6倍,而4-羟普萘洛尔的AUC基本不变,导致稳态时4-羟普萘洛尔/普萘洛尔血药浓度比率相对降低,提示普萘洛尔的羟化代谢属于零级动力学过程。普萘洛尔和4-羟普萘洛尔抑制运动心率的最大效应Emax为37.2±12.7%,半效血药浓度Css50为44.66±35.24ng/ml,药效半衰期t1/2keo为(8.78士2.27h),显著长于普萘洛尔血药浓度半衰期(4.32±2.17h),故临床上以药效半衰期决定用药方案更为合理。

The aim of this study was to investigate the correlation of beta-adrenoceptor block-ing activity against plasma concentration of propranolol(PPL) and its active metabolite 4-hydroxypro-pranolol (4-OH-P) in 20 healthy volunteers, and to establish the pharmacokinetic-pharmacodynamicunited model of propranolol. After oral administration of propranolol,the suppressive effects on heart rates and blood pressurewere more remarkable during exercise than that at rest. Posture had little effect on the reduction ofblood pressure. There was significant correlation between plasma concentration and the suppressive ef-fects during exercise, but poor compliance with the effects at rest. when plasma level of propranololplus that of 4-OH-P, the concentration-effect correlation will be improved in comparison with onlypropranolol (p<0.05). At steady-state the AUC of propranolol was increased by 1.6 times, compared with single doses,but no change for the AUC of 4-OH-P. Thus, the average steady-state concentration ratio for 4-OH-P/PPL went down relatively, which suggested that there was a decrease in intrinsic hepatic clea-rance of propranolol, leading to an increase in bioavailability at steady-state. The maximal pharmacological effect of inhibiting heart rates (Emax) were 37.2±12.7%. TheCss50, plasma concentration producing 50% Emax, were 44.66±35.24ng/ml. The half-life ofpharmacodynamics for cardiac suppressive effect of propranolol was significantly longer than that ofpharmacokinetics (t1/2Keo: 8.78±2.27 vs t1/2K: 4.32±2.17h, p<0. 01). Therefore, the design ofrational dosing regimens for clinical therapeutics must be performed by combined application of theprinciples of pharmacokinetics and pharmacodynamics.