Satterwhite J H, Boudinot F D
Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602-2353, USA.
Exp Gerontol. 1995 Sep-Oct;30(5):505-15. doi: 10.1016/0531-5565(95)00012-6.
The pharmacodynamics of naproxen were evaluated in 5- and 24-month-old male Fischer 344 rats. Plasma naproxen concentrations and thromboxane B2 (TxB2) concentrations were measured as a function of time after intravenous administration of 25 mg/kg naproxen. Age-dependent alterations in naproxen pharmacokinetics were attributed to significant reductions in free plasma clearance (CLfree) and free steady-state volume of distribution (VSSfree), suggesting a decline in metabolic activity and naproxen binding to tissue components in aged rats, respectively. The time course of TxB2 production as a function of unbound naproxen concentrations was described by a sigmoid Emax model. Age had no significant effect on the pharmacodynamic parameter Emax, the maximum percent inhibition of TxB2 formation. Age also had no statistically significant effect on EC50, the drug concentration producing 50% of the maximum effect, however, average EC50 values were 35% higher in the aged rats. The duration of TxB2 inhibition was unaffected by age, possibly owing to similar relative decreases in receptor sensitivity (increased EC50) and increases in free naproxen concentrations (decreased free clearance and volume of distribution). Alternatively, the age-related changes in pharmacokinetic parameters were not of sufficient magnitude to produce a significant change in drug response, naproxen, pharmacokinetics, pharmacodynamics, age, rats, thromboxane B2, nonsteroidal anti-inflammatory drugs.
在5月龄和24月龄的雄性Fischer 344大鼠中评估了萘普生的药效学。静脉注射25mg/kg萘普生后，测定血浆萘普生浓度和血栓素B2（TxB2）浓度随时间的变化。萘普生药代动力学的年龄依赖性改变归因于游离血浆清除率（CLfree）和游离稳态分布容积（VSSfree）的显著降低，分别提示老年大鼠代谢活性下降和萘普生与组织成分的结合减少。TxB2产生的时间过程作为未结合萘普生浓度的函数，用S形Emax模型描述。年龄对药效学参数Emax（TxB2形成的最大抑制百分比）无显著影响。年龄对产生最大效应50%的药物浓度EC50也无统计学显著影响，然而，老年大鼠的平均EC50值高35%。TxB2抑制的持续时间不受年龄影响，可能是由于受体敏感性相对降低（EC50增加）和游离萘普生浓度增加（游离清除率和分布容积降低）相似。或者，药代动力学参数的年龄相关变化幅度不足以产生药物反应的显著变化，萘普生，药代动力学，药效学，年龄，大鼠，血栓素B2，非甾体抗炎药。
