School of Physiology and Pharmacology, University of NSW, 2052, Sydney, Australia.
Inflammopharmacology. 1999;7(3):255-63. doi: 10.1007/s10787-999-0008-x.
There is much uncertainty about the mechanism of action of paracetamol (acetaminophen). It is commonly stated that, unlike the non-steroidal anti-inflammatory drugs (NSAIDs), it is a weak inhibitor of the synthesis of prostaglandins. This conclusion is made largely from studies in which the synthesis of prostaglandins was measured in homogenized tissues. However, in several cellular systems, paracetamol is an inhibitor of the synthesis of prostaglandins with IC(50) values ranging from approximately 4 microM to 200 microM. Paracetamol is not bound significantly to plasma proteins and therefore the concentrations in plasma can be equated directly with those used in in vitro experiments. After oral doses of 1 g, the peak plasma concentrations of paracetamol are approximately 100 microM and the plasma concentrations are therefore in the range where marked inhibition of the synthesis of prostaglandins should occur in some cells. Paracetamol is metabolized by the peroxidase component of prostaglandin H synthase but the relationship of this to inhibition of the cyclooxygenase or peroxidase activities of the enzyme is unclear. Paracetamol is also metabolized by several other peroxidases, including myeloperoxidase, the enzyme in neutrophils which is responsible for the production of hypochlorous acid (HOCl). The metabolism of paracetamol by myeloperoxidase leads to the decreased total production of HOC1 by both intact neutrophils and isolated myeloperoxidase, even though the initial rate of production of HOC1 is increased. The IC(50) value, derived from inhibition of the total production of HOC1 by isolated myeloperoxidase, is 81 microM. Several NSAIDs inhibit functions of neutrophils in media containing low concentrations of protein but their effects, in contrast to that of paracetamol, are generally produced only at concentrations greater than those of the unbound drug in plasma during treatment with the NSAIDs. However, neutrophils isolated during treatment with NSAIDs, such as piroxicam, ibuprofen and indomethacin show decreased function. Paracetamol has little or no anti-inflammatory activity by itself but may potentiate the clinical activity of NSAIDs in the treatment of rheumatoid arthritis.
对乙酰氨基酚（扑热息痛）的作用机制存在许多不确定性。通常认为，与非甾体抗炎药（NSAIDs）不同，它是前列腺素合成的弱抑制剂。这一结论主要是基于对匀浆组织中前列腺素合成进行测量的研究得出的。然而，在一些细胞系统中，扑热息痛是一种具有 IC 50 值范围在约 4 至 200 微摩尔的前列腺素合成抑制剂。扑热息痛与血浆蛋白结合不显著，因此血浆中的浓度可以直接与体外实验中使用的浓度等同。口服 1 克后，扑热息痛的血浆峰浓度约为 100 微摩尔，因此在一些细胞中，前列腺素合成的明显抑制应该发生在血浆浓度范围内。扑热息痛通过前列腺素 H 合酶的过氧化物酶成分代谢，但这与酶的环氧化酶或过氧化物酶活性的抑制之间的关系尚不清楚。扑热息痛也被几种其他过氧化物酶代谢，包括髓过氧化物酶，这种酶存在于中性粒细胞中，负责产生次氯酸（HOCl）。髓过氧化物酶代谢扑热息痛会导致完整中性粒细胞和分离的髓过氧化物酶产生的 HOCl 总量减少，尽管 HOCl 的初始产生速率增加。从分离的髓过氧化物酶对 HOCl 总量产生的抑制中得出的 IC 50 值为 81 微摩尔。几种 NSAIDs 抑制含低浓度蛋白质介质中的中性粒细胞的功能，但与扑热息痛不同，它们的作用通常仅在治疗期间 NSAIDs 中未结合药物的血浆浓度大于这些浓度时才会产生。然而，在 NSAIDs 治疗期间分离出的中性粒细胞，如吡罗昔康、布洛芬和吲哚美辛，显示出功能下降。扑热息痛本身几乎没有或没有抗炎活性，但它可能增强 NSAIDs 在治疗类风湿关节炎中的临床活性。
