Satterwhite J H, Boudinot F D
College of Pharmacy, University of Georgia, Athens.
J Gerontol. 1991 Nov;46(6):B222-7. doi: 10.1093/geronj/46.6.b222.
The effects of age and dose on the pharmacokinetics of naproxen were evaluated in young and senescent male Fischer 344 rats after 2.5 and 25 mg/kg doses. Pharmacokinetic parameters based on free naproxen concentrations demonstrated a significant decrease in free clearance and free steady-state volume of distribution in the aged rats. In vitro enzyme kinetic studies also demonstrated an age-related decline in the metabolic activity and affinity of the metabolic enzymes for naproxen in the aged rats. Plasma protein binding studies revealed a larger free fraction of drug in the plasma of senescent rats. Total clearance and steady-state volume of distribution were indistinguishable between young and old rats owing to the higher free fraction in aged rats. Dose had a significant effect with free clearance and free volume of distribution decreasing as dose increased. The binding of naproxen to plasma proteins was dependent on drug concentration. Unlike the parameters based on free naproxen concentrations, total plasma clearance and volume of distribution increased with increasing dose, due to the nonlinear protein binding.
在年轻和衰老的雄性Fischer 344大鼠中，给予2.5和25 mg/kg剂量后，评估了年龄和剂量对萘普生药代动力学的影响。基于游离萘普生浓度的药代动力学参数表明，老年大鼠的游离清除率和游离稳态分布容积显著降低。体外酶动力学研究还表明，老年大鼠代谢酶的代谢活性和对萘普生的亲和力随年龄增长而下降。血浆蛋白结合研究显示，衰老大鼠血浆中药物的游离分数更大。由于老年大鼠游离分数较高，年轻和老年大鼠的总清除率和稳态分布容积无明显差异。剂量对游离清除率和分布容积有显著影响，随着剂量增加，两者均降低。萘普生与血浆蛋白的结合取决于药物浓度。与基于游离萘普生浓度的参数不同，由于非线性蛋白结合，总血浆清除率和分布容积随剂量增加而增加。
