Holzer P, Jocic M, Cabré F, Mauléon D
Department of Experimental and Clinical Pharmacology, University of Graz, Austria.
Inflamm Res. 2001 Dec;50(12):602-8. doi: 10.1007/PL00000241.
Since assessment of the acute gastrotoxicity of nonsteroidal antiinflammatory drugs (NSAIDs) in rats requires high doses of the drugs, we sought to establish an experimental model with which this adverse NSAID effect can be estimated at therapy-relevant doses.
The study was performed with racemic flurbiprofen-trometamol (R/S-FBP), its pure enantiomers S-FBP and R-FBP, and racemic ketoprofen-trometamol (R/S-KP). Two hours after administration of FBP or KP to Sprague-Dawley rats, HCl (0.5 M, 10 ml/kg) was given intragastrically (IG), and the haemorrhagic lesion area in the gastric mucosa quantified 1 h post-HCI.
FBP amplified gastric acid injury in a dose-related manner, the rank order of potency being S-FBP > R/S-FBP >> R-FBP. While less than 1 micromol/kg S-FBP and R/S-FBP aggravated acid injury, doses up to 50 micromol/kg failed to cause appreciable damage without subsequent HCl challenge. Similar observations were made with R/S-KP which at doses of > or = 1 micromol/kg aggravated gastric acid injury. There was no significant difference in the gastrotoxicity of FBP when the drug was administered subcutaneously or IG, whereas subcutaneously injected R/S-KP was slightly more toxic than IG R/S-KP.
These data show that FBP- and KP-induced amplification of acid injury in the rat gastric mucosa is a sensitive assay whereby, with single drug dosing, the gastrotoxic potential of these and other NSAIDs may be estimated at therapy-relevant doses that in humans threaten mucosal integrity only following chronic use.
由于评估非甾体抗炎药（NSAIDs）对大鼠的急性胃毒性需要高剂量药物，我们试图建立一种实验模型，通过该模型可以在与治疗相关的剂量下评估NSAIDs的这种不良作用。
使用外消旋氟比洛芬- trometamol（R/S-FBP）、其纯对映体S-FBP和R-FBP以及外消旋酮洛芬- trometamol（R/S-KP）进行研究。给Sprague-Dawley大鼠施用FBP或KP两小时后，经胃内（IG）给予HCl（0.5 M，10 ml/kg），并在给予HCl后1小时对胃黏膜中的出血损伤面积进行定量。
FBP以剂量相关的方式放大胃酸损伤，效力顺序为S-FBP>R/S-FBP>>R-FBP。小于1微摩尔/千克的S-FBP和R/S-FBP加重了酸损伤，而高达50微摩尔/千克的剂量在没有随后HCl刺激的情况下未能造成明显损伤。对于R/S-KP也有类似观察结果，其剂量≥1微摩尔/千克时加重了胃酸损伤。当药物皮下注射或经胃内给药时，FBP的胃毒性没有显著差异，而皮下注射的R/S-KP比经胃内注射的R/S-KP毒性略大。
这些数据表明，FBP和KP诱导的大鼠胃黏膜酸损伤放大是一种敏感的检测方法，通过单次给药，可以在与治疗相关的剂量下评估这些和其他NSAIDs的胃毒性潜力，在人类中，这些剂量仅在长期使用后才会威胁黏膜完整性。
