Brune K, Geisslinger G, Menzel-Soglowek S
Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuernberg, Germany.
J Clin Pharmacol. 1992 Oct;32(10):944-52. doi: 10.1002/j.1552-4604.1992.tb04643.x.
The mode of action of aspirinlike drugs in pain is widely referred to as inhibition of prostaglandin synthesis. Salicylic acid, however, at low doses, is an analgesic but not a potent anti-inflammatory agent. This "enigma" may be resolved by recent findings employing 2-arylpropionic acids. Pure enantiomers of these chiral drugs show a different pharmacodynamic and pharmacokinetic profile. Using pure enantiomers of flurbiprofen, ibuprofen, and ketoprofen, we could show that (1) R-enantiomers of these drugs are inverted to S-enantiomers to a different degree in different species, including humans, (2) the pharmacokinetic parameters of both pure enantiomers differ in a drug- and a species-specific manner, and (3) both enantiomers exert differential analgesic effects. It appears particularly interesting that R-flurbiprofen, for instance, which is not or only to a small extent inverted in humans and rats, is practically devoid of prostaglandin synthesis inhibition in vitro. Consequently, in line with current thinking, R-flurbiprofen is not toxic to the gastrointestinal tract and shows no anti-inflammatory effects. In contrast to current concepts, however, this enantiomer does exert analgesic activity in different models of pain and nociception. It is concluded that R-flurbiprofen and, possibly, other R-enantiomers of 2-arylpropionic acids may exert novel analgesic effects independently of peripheral prostaglandin synthesis inhibition in inflamed tissue.
阿司匹林类药物的止痛作用方式被广泛认为是抑制前列腺素合成。然而，低剂量的水杨酸是一种镇痛药，但不是强效抗炎药。利用2-芳基丙酸的最新研究结果或许可以解开这个“谜团”。这些手性药物的纯对映体表现出不同的药效学和药代动力学特征。使用氟比洛芬、布洛芬和酮洛芬的纯对映体，我们能够证明：（1）在包括人类在内的不同物种中，这些药物的R-对映体以不同程度转化为S-对映体；（2）两种纯对映体的药代动力学参数因药物和物种而异；（3）两种对映体发挥不同的镇痛作用。特别有趣的是，例如，在人类和大鼠中不会或仅在很小程度上发生转化的R-氟比洛芬，在体外几乎没有抑制前列腺素合成的作用。因此，按照目前的观点，R-氟比洛芬对胃肠道无毒，也没有抗炎作用。然而，与目前的概念相反，这种对映体在不同的疼痛和伤害感受模型中确实具有镇痛活性。得出的结论是，R-氟比洛芬以及可能的其他2-芳基丙酸的R-对映体可能独立于炎症组织中前列腺素合成的抑制而发挥新的镇痛作用。
