Schweitzer A, Hasler-Nguyen N, Zijlstra J
Department of Preclinical Development, Novartis Consumer Health, Rte Etraz, Nyon, Switzerland.
BMC Pharmacol. 2009 Mar 16;9:5. doi: 10.1186/1471-2210-9-5.
Diclofenac is a nonsteroidal anti-inflammatory drug which is available as prescription (RX) and over-the-counter (OTC) medication for the systemic and topical treatment of painful and inflammatory conditions such as arthritis and back pain. This study was undertaken to investigate the distribution and retention of diclofenac and/or its metabolites in inflamed tissues, using the carrageenan-induced inflammation model and quantitative whole body autoradiography in rats.
[14C]diclofenac sodium was administrated as a single 2 mg/kg oral dose 1 h after injection of carrageenan into one front and one hind footpads and subcutaneously into the dorsum of the neck of rats. A control animal received saline injections. Three carrageenan-treated rats and one control rat were sacrificed at 1, 4, 8, and 24 h after [14C]diclofenac sodium administration (total of 4 rats/time point). The carcasses were immediately snap-frozen and prepared for cryosectioning. Lengthwise whole-body sections (40 microm thick), including all major tissues, were obtained from different levels across the body. The tissue concentrations of total radiolabeled components were determined using quantitative autoradioluminography.
The radioactivity patterns demonstrated that diclofenac and/or its metabolites preferentially distributed into the inflamed tissues. In unharmed tissues the distribution was similar in control and treated animals. The exposure, based on the areas under the tissue concentration versus time (AUC(0-tlast)), was 26 and 53 fold higher in the inflamed neck and inflamed footpads of treated animals than in control rats; the exposures in unharmed tissues were similar in the treated and control rats, and the AUC(0-tlast) was 17 fold higher in the inflamed paws than in the non inflamed footpads of the carrageenan-treated rats. The higher exposure in the inflamed tissues may be explained partly to the fact that the elimination of total radiolabeled components from inflamed tissues (t(1/2) = 6 h) appeared lower than from the corresponding unharmed tissues (t(1/2) = 2 h).
This animal study demonstrated that diclofenac and/or its metabolites were rapidly and preferentially taken up and retained in inflamed tissues. Although there were theoretical considerations that mildly acidic NSAID may show some preferential distribution in inflamed tissues there was no clear experimental proof for diclofenac until the present study.
双氯芬酸是一种非甾体抗炎药，有处方药（RX）和非处方药（OTC）两种剂型，可用于全身和局部治疗疼痛和炎症性疾病，如关节炎和背痛。本研究采用角叉菜胶诱导的炎症模型和大鼠定量全身放射自显影技术，研究双氯芬酸及其代谢产物在炎症组织中的分布和滞留情况。
在大鼠的一只前足垫和一只后足垫注射角叉菜胶1小时后，以及在大鼠颈部背部皮下注射角叉菜胶1小时后，以2mg/kg的剂量单次口服给予[14C]双氯芬酸钠。一只对照动物接受生理盐水注射。在给予[14C]双氯芬酸钠后1、4、8和24小时处死3只经角叉菜胶处理的大鼠和1只对照大鼠（每个时间点共4只大鼠）。将尸体立即速冻并准备进行冷冻切片。从身体不同水平获取包括所有主要组织的纵向全身切片（40微米厚）。使用定量放射自显影法测定总放射性标记成分的组织浓度。
放射性分布模式表明，双氯芬酸及其代谢产物优先分布于炎症组织中。在未受损组织中，对照动物和处理动物的分布相似。根据组织浓度与时间曲线下面积（AUC(0 - tlast)）计算，处理动物炎症颈部和炎症足垫的暴露量分别比对照大鼠高26倍和53倍；处理大鼠和对照大鼠在未受损组织中的暴露量相似，且角叉菜胶处理大鼠炎症爪子的AUC(0 - tlast)比未发炎足垫高17倍。炎症组织中较高的暴露量部分原因可能是炎症组织中总放射性标记成分的消除（t(1/2) = 6小时）似乎低于相应的未受损组织（t(1/2) = 2小时）。
本动物研究表明，双氯芬酸及其代谢产物迅速且优先被炎症组织摄取并滞留。尽管从理论上考虑，轻度酸性的非甾体抗炎药可能在炎症组织中表现出一些优先分布，但在本研究之前，双氯芬酸尚无明确的实验证据。
