萘丁美酮的临床药代动力学。选择性环氧合酶2抑制作用的曙光？,Clinical Pharmacokinetics

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萘丁美酮的临床药代动力学。选择性环氧合酶2抑制作用的曙光？
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 1998-01-22 , DOI: 10.2165/00003088-199733060-00001
N M Davies ₁

Affiliation

萘丁美酮是2,6-二取代萘基-烷酮类的非甾体抗炎药（NSAID）。萘丁美酮被代谢成活性代谢物6-甲氧基-2-萘乙酸（6-MNA），这是一种相对选择性的环加氧酶2抑制剂，具有抗炎和镇痛作用。萘丁美酮及其代谢产物广泛结合血浆白蛋白。生物转化为6-MNA后，萘丁美酮被消除，后者不经历肝肠循环，相应的糖共轭物代谢物从尿中排出。在滑液中可达到6-MNA的大量浓度，这是他提出的在慢性炎症性关节病中的作用部位。与单剂量相比，稳态时血浆浓度-时间曲线（AUC）下的面积更小。这可能是由于分布体积增加和蛋白质结合饱和所致。对于该NSAID，尚需阐明6-MNA浓度与治疗和毒理作用之间的关系。肾功能衰竭会显着减少6-MNA的消除，但6-MNA的稳态浓度不会增加，可能是由于非线性蛋白结合所致。与年轻健康志愿者相比，老年骨关节炎患者表现出减少的消除作用和萘丁美酮的血浆浓度升高。风湿性疾病的活动也影响6-MNA血浆浓度，因为患有活动性疾病且血清白蛋白浓度较低的患者在血浆浓度与时间的关系曲线下面积较小。严重肝功能不全患者中6-MNA的生物利用度降低也很明显。老年人，活动性风湿病患者和肝功能不全患者可能需要调整剂量，但轻度至中度肾衰竭患者则无需调整剂量。

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Clinical pharmacokinetics of nabumetone. The dawn of selective cyclo-oxygenase-2 inhibition?

Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) of the 2,6-disubstituted naphthyl-alkanone class. Nabumetone is metabolised to an active metabolite 6-methoxy-2-napthylacetic acid (6-MNA) which is a relatively selective cyclo-oxygenase-2 inhibitor that has anti-inflammatory and analgesic properties. Nabumetone and its metabolites bind extensively to plasma albumin. Nabumetone is eliminated following biotransformation to 6-MNA, which does not undergo enterohepatic circulation and the respective glucoroconjugated metabolites are excreted in urine. Substantial concentrations of 6-MNA are attained in synovial fluid, which is he proposed site of action in chronic inflammatory arthropathies. A smaller area under the plasma concentration-time curve (AUC) is evident at steady state as compared with a single dose; this is possibly due to an increase in the volume of distribution and saturation of protein binding. Relationships between 6-MNA concentrations and the therapeutic and toxicological effects have yet to be elucidated for this NSAID. Renal failure significantly reduces 6-MNA elimination but steady-state concentrations of 6-MNA are not increased, possibly because of nonlinear protein binding. Elderly patients with osteoarthritis demonstrate decreased elimination and increased plasma concentrations of nabumetone as compared with young healthy volunteers. Rheumatic disease activity also influences 6-MNA plasma concentrations, as patients with more active disease and lower serum albumin concentrations demonstrate a lower area under the plasma concentration versus time curve. A reduced bioavailability of 6-MNA in patients with severe hepatic impairment is also evident. Dosage adjustment may be required in the elderly, patients with active rheumatic disease and those with hepatic impairment, but not in patients with mild-to-moderate renal failure.

更新日期：2019-11-01

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