Shirakawa Kenshu, Takeno Masafumi, Kuma Hidekazu, Terahara Takaaki, Yamaguchi Shigeki
Department of Anesthesiology and Pain Medicine, Dokkyo Medical University School of Medicine, Tochigi, Japan.
Hisamitsu Pharmaceutical Co., Inc., Tokyo, Japan.
Pain Ther. 2025 Feb;14(1):329-338. doi: 10.1007/s40122-024-00687-2. Epub 2024 Dec 17.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for pain disorders and exert pharmacological effects by inhibiting cyclooxygenase (COX). Although previous studies have evaluated the COX inhibitory activity and selectivity of NSAIDs, none has compared COX inhibitory concentrations with the plasma concentrations of clinical doses or investigated the efficacy and adverse effects of different dosage forms. Therefore, in this study we evaluated the COX inhibitory activities and inhibition rates of clinical doses of the various NSAID formulations, especially diclofenac sodium.
Human blood and the drug (diclofenac sodium, celecoxib, ibuprofen, flurbiprofen, or etodolac) were mixed and incubated, and the supernatant was collected and quantified the COX inhibitory activity of each drug by ELISA. Logistic regression analyses were used to calculate the inhibition rates at maximum plasma drug concentration (C) of clinical doses of marketed formulations. For diclofenac sodium, we also calculated the concentrations at which COX inhibition rates were 50% and 80% (IC and IC).
COX-2 inhibition rate at C of clinical doses exceeded 50% except celecoxib 100 mg. For diclofenac sodium, the C at the clinical doses of the oral and suppository formulations showed almost complete inhibition of COX-2 and an inhibition rate exceeding IC for COX-1. The C at repeated doses of the transdermal formulation showed an inhibition rate above IC for COX-2 but below IC for COX-1.
This result explains why gastrointestinal disorders frequently occur with oral and suppository formulations of diclofenac sodium despite its relatively high COX-2 selectivity. Although the plasma drug concentration of the transdermal formulation is lower than oral and suppository formulations, it has an inhibition rate above IC for COX-2, which is required for analgesic efficacy, and has a lower COX-1 inhibition rate than these formulations.
The findings explain why the transdermal formulation exerts an analgesic effect despite having a lower C than other diclofenac sodium formulations.
非甾体抗炎药（NSAIDs）常用于疼痛性疾病，通过抑制环氧化酶（COX）发挥药理作用。尽管先前的研究评估了NSAIDs的COX抑制活性和选择性，但尚无研究比较COX抑制浓度与临床剂量的血浆浓度，或研究不同剂型的疗效和不良反应。因此，在本研究中，我们评估了各种NSAID制剂临床剂量的COX抑制活性和抑制率，尤其是双氯芬酸钠。
将人体血液与药物（双氯芬酸钠、塞来昔布、布洛芬、氟比洛芬或依托度酸）混合并孵育，收集上清液，通过酶联免疫吸附测定法（ELISA）对每种药物的COX抑制活性进行定量。采用逻辑回归分析计算市售制剂临床剂量在最大血浆药物浓度（C）时的抑制率。对于双氯芬酸钠，我们还计算了COX抑制率为50%和80%时的浓度（IC50和IC80）。
除塞来昔布100mg外，临床剂量的C时COX - 2抑制率超过50%。对于双氯芬酸钠，口服和栓剂剂型临床剂量的C显示对COX - 2几乎完全抑制，对COX - 1的抑制率超过IC50。透皮制剂重复给药时的C显示对COX - 2的抑制率高于IC50，但对COX - 1的抑制率低于IC50。
该结果解释了为什么尽管双氯芬酸钠具有相对较高的COX - 2选择性，但口服和栓剂剂型仍频繁出现胃肠道疾病。尽管透皮制剂的血浆药物浓度低于口服和栓剂剂型，但其对COX - 2的抑制率高于IC50，这是镇痛效果所必需的，且对COX - 1的抑制率低于这些剂型。
这些发现解释了为什么透皮制剂尽管C低于其他双氯芬酸钠制剂却仍能发挥镇痛作用。
