Khazaeinia Tahereh, Jamali Fakhreddin
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
J Pharm Pharm Sci. 2003 Sep-Dec;6(3):352-9.
Gastrointestinal (GI) side effects of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac may be reduced if it is administered as a complex with phospholipid. The upper and lower GI permeability induced by a diclofenac-dipalmitoyl phosphatidyl choline (DPPC) complex were compared with those of diclofenac acid and its sodium salt in rats.
Pharmacokinetic studies were carried out to assess bioavailability of diclofenac preparations. Adult male Sprague-Dawley rats were dosed orally (equivalent to 15 mg/kg diclofenac sodium) as the acid or its sodium salt as well as diclofenac-DPPC complex. Upper and lower GI permeability, as surrogate markers of toxicity were determined using sucrose and 51Cr-EDTA, respectively.
At 1 h post-dose only diclofenac sodium induced a significant increased upper GI permeability. Three h post-dose all formulations significantly increased upper GI permeability although the diclofenac acid had the least effect. In the lower GI tract, the induced increase in permeability was significant at 1 and 3 h post-dose for all formulations with no significant differences between them.
The induced upper and lower GI toxicity of diclofenac was formulation and time dependent. The lack of effect of diclofenac acid was due to the decreased availability of the drug. In the upper GI tract, up to 1 h post-dose, the diclofenac-DPPC complex demonstrated reduced upper gastroduodenal permeability as measured by sucrose. However, the protective effect of DPPC did not last and was not extended to the lower GI tract due to the systemic effect, contribution from the enterohepatic recirculation and/or dissociation of the complex. In assessing diclofenac GI toxicity, the effect of the different formulations on the entire GI tract at various times after drug administration must be considered.
如果非甾体抗炎药双氯芬酸以与磷脂形成的复合物形式给药，其胃肠道（GI）副作用可能会降低。将双氯芬酸 - 二棕榈酰磷脂酰胆碱（DPPC）复合物诱导的大鼠上、下胃肠道通透性与双氯芬酸及其钠盐的通透性进行比较。
进行药代动力学研究以评估双氯芬酸制剂的生物利用度。成年雄性Sprague - Dawley大鼠口服给药（相当于15mg/kg双氯芬酸钠），剂型为酸、钠盐以及双氯芬酸 - DPPC复合物。分别使用蔗糖和51Cr - EDTA测定上、下胃肠道通透性，作为毒性的替代标志物。
给药后1小时，仅双氯芬酸钠显著增加上胃肠道通透性。给药后3小时，所有制剂均显著增加上胃肠道通透性，尽管双氯芬酸的作用最小。在下胃肠道，给药后1小时和3小时，所有制剂诱导的通透性增加均显著，且它们之间无显著差异。
双氯芬酸诱导的上、下胃肠道毒性具有剂型和时间依赖性。双氯芬酸作用不明显是由于药物可用性降低。在上胃肠道，给药后1小时内，通过蔗糖测定，双氯芬酸 - DPPC复合物显示上胃十二指肠通透性降低。然而，DPPC的保护作用未持续，且由于全身作用、肠肝循环的贡献和/或复合物的解离，未扩展至下胃肠道。在评估双氯芬酸的胃肠道毒性时，必须考虑不同制剂在给药后不同时间对整个胃肠道的影响。
