Effect of drug release rate on therapeutic outcomes: Formulation dependence of gastrointestinal toxicity of diclofenac in the rat

The use of the non-steroidal anti-inflammatory drug, diclofenac, is associated with occasional serious side effects in the gastrointestinal (GI) tract. We examined the effect of altering the site of release of diclofenac sodium on GI tract side effects. Dissolution and pharmacokinetic studies were carried out to substantiate the sustained-release nature of crushed sustained release tablet. Adult male Sprague-Dawley rats were administered diclofenac 10 mg/kg orally as either immediate-release or sustained-release preparations. Upper and lower GI permeability, as a surrogate marker of toxicity, were measured using sucrose and 51Cr-EDTA, respectively. Immediate- and sustained-release preparations similarly increased upper GI permeability. The induced toxicity in the lower GI tract, however, caused by the sustained-release formulation lasted longer than that of the immediate release formulation. Since both immediate- and sustained-release preparations of diclofenac increased sucrose permeability, the upper GI damage caused by diclofenac may be attributable mainly to a systemic mechanism. The prolonged lower GI toxicity following the sustained-release preparation may be related to a greater residence time therein.