Hinz Burkhard, Cheremina Olga, Bachmakov Jouri, Renner Bertold, Zolk Oliver, Fromm Martin F, Brune Kay
Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany.
FASEB J. 2007 Aug;21(10):2343-51. doi: 10.1096/fj.06-8061com. Epub 2007 Apr 13.
Dipyrone (INN, metamizol) is a common analgesic used worldwide. Its widespread prescription or over-the-counter use in many countries (e.g., Brazil, Israel, Mexico, Russia, Spain) requires insight into its mode of action. This study therefore addressed the impact of its metabolites 4-methyl-amino-antipyrine (MAA) and 4-amino-antipyrine (AA) on peripheral cyclooxygenases (COX). Pharmacokinetics of metabolites and ex vivo COX inhibition were assessed in five volunteers receiving dipyrone at single oral doses of 500 or 1000 mg. Coagulation-induced thromboxane B2 formation and lipopolysaccharide-induced prostaglandin E2 synthesis were measured in vitro and ex vivo in human whole blood as indices of COX-1 and COX-2 activity. In vitro, metabolites elicited no substantial COX-1/COX-2 selectivity with MAA (IC50=2.55 micromol/L for COX-1; IC50=4.65 micromol/L for COX-2), being approximately 8.2- or 9-fold more potent than AA. After administration of dipyrone, MAA plasma concentrations remained above the IC50 values for each isoform for at least 8 h (500 mg) and 12 h (1000 mg) postdose. COX inhibition correlated with MAA plasma levels (ex vivo IC50 values of 1.03 micromol/L [COX-1] and 0.87 micromol/L [COX-2]). By contrast, plasma peak concentrations of AA after the 1000 mg dose were 2.8- and 6.5-fold below its IC50 values for COX-1 and COX-2, respectively. Maximal inhibitions of COX-1 and COX-2 were 94% and 87% (500 mg), 97% and 94% (1000 mg). Taken together, dipyrone elicits a substantial and virtually equipotent inhibition of COX isoforms via MAA. Given the profound COX-2 suppression by dipyrone, which was considerably above COX-2 inhibition by single analgesic doses of celecoxib and rofecoxib, a significant portion of its analgesic action may be ascribed to peripheral mechanisms. In view of the observed COX-1 suppression, physicochemical factors (lack of acidity) rather than differential COX-1 inhibition may be responsible for dipyrone's favorable gastrointestinal tolerability compared with acidic COX inhibitors.
安乃近（国际非专利药品名称，甲氨基安替比林）是一种在全球广泛使用的普通镇痛药。它在许多国家（如巴西、以色列、墨西哥、俄罗斯、西班牙）被广泛用于处方或非处方用途，因此需要深入了解其作用方式。本研究因此探讨了其代谢产物4-甲基氨基安替比林（MAA）和4-氨基安替比林（AA）对周围环氧化酶（COX）的影响。在五名志愿者单次口服500或1000毫克安乃近后，评估了代谢产物的药代动力学和体外COX抑制作用。在体外和人体全血中测量凝血诱导的血栓素B2形成和脂多糖诱导的前列腺素E2合成，作为COX-1和COX-2活性的指标。在体外，代谢产物对COX-1/COX-2没有明显的选择性，MAA（COX-1的IC50 = 2.55微摩尔/升；COX-2的IC50 = 4.65微摩尔/升），其效力比AA高约8.2倍或9倍。服用安乃近后，MAA血浆浓度在给药后至少8小时（500毫克）和12小时（1000毫克）内保持高于每种同工型的IC50值。COX抑制作用与MAA血浆水平相关（体外IC50值分别为1.03微摩尔/升[COX-1]和0.87微摩尔/升[COX-2]）。相比之下，1000毫克剂量后AA的血浆峰值浓度分别比其COX-1和COX-2的IC50值低2.8倍和6.5倍。COX-1和COX-2的最大抑制率分别为94%和87%（500毫克），97%和94%（1000毫克）。综上所述，安乃近通过MAA对COX同工型产生显著且几乎等效的抑制作用。鉴于安乃近对COX-2的强烈抑制作用，大大高于单剂量塞来昔布和罗非昔布对COX-二的抑制作用，其镇痛作用的很大一部分可能归因于外周机制。鉴于观察到的COX-1抑制作用，与酸性COX抑制剂相比，安乃近良好的胃肠道耐受性可能是由于物理化学因素（缺乏酸性）而非不同的COX-1抑制作用。
