Oral absorption and pharmacokinetics of rebamipide and rebamipide lysinate in rats.
ABSTRACT Rebamipide is an anti-ulcer agent exhibiting a low aqueous solubility and a poor oral bioavailability. This study was conducted to examine if the rebamipide lysinate salt form would exhibit improved solubility profiles and higher oral bioavailability compared with rebamipide free acid. Both compounds showed pH-dependent solubility profiles, with the solubility of rebamipide lysinate dramatically improved at a median pH of 5.1 (17-fold increases) over free acid, but the improvement in the solubility was not as pronounced in artificial gastric and intestinal fluids (1.4- and 1.9-fold increases, respectively). The Cl, V(ss) and t1/2 in rats after i.v. injection of rebamipide (0.5 mg/kg) averaged 21.0 +/- 3.2 ml/min/kg, 0.3 +/- 0.0 L/kg, and 0.4 +/- 0.1 hr, respectively. No significant difference was observed in these parameters between rebamipide and rebamipide lysinate. Despite improved solubility profiles, the absolute oral bioavailability of rebamipide lysinate was not increased (5.1 vs. 4.8%) nor did AUC (407.8 vs. 383.6 ng x hr/ml) and C(max) (87.4 vs. 77.0 ng/ml) compared with rebamipide free acid. Rebamipide lysinate, however, showed a more rapid absorption, and initial serum drug concentrations were higher than those found for rebamipide free acid.
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ABSTRACT: The purpose of this study was to improve the gastric solubility and bioavailability of rebamipide (RBM) by preparing the RBM solid dispersion tablet (RBM-SDT) from solid dispersion powder prepared by spray-drying technique. For preparation of rebamipide solid dispersions (RBM-SDs), solubility study was performed in various hydrophilic carriers and alkalizers, among which sodium alginate and sodium carbonate were selected as the hydrophilic polymer and alkalizer, respectively. Different combinations of drug-polymer-alkalizer were dissolved in aqueous solution and spray-dried in order to obtain solid dispersions. Noticeable improvement in aqueous solubility (approximately 200 times) and in vitro dissolution rate was observed by RBM-SDs, compared to RBM powder. The optimized formulation of RBM-SD powder consisted of RBM powder/sodium alginate/sodium carbonate at the weight ratio of 1/2/2. The transformation of crystalline RBM to amorphous RBM-SD powder was clearly demonstrated by powder X-ray diffraction, differential scanning calorimetry (DSC) and scanning electron microscopy. The optimized RBM-SD was formulated in tablet dosage form, containing approximately 2 % sodium lauryl sulphate and poloxamer F68 as wetting agents. The RBM-SDT exhibited enhanced dissolution in hydrochloric acid buffer (pH 1.2) and distilled water. Moreover, pharmacokinetic study in rats showed higher AUC and Cmax for RBM-SDT than those for RBM powder and commercial product. Thus, the developed RBM-SDT formulation can be more efficacious for improving oral bioavailability of RBM.Archives of Pharmacal Research 06/2014; 38(4). DOI:10.1007/s12272-014-0399-0 · 1.75 Impact Factor
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ABSTRACT: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is primarily limited by renal and gastrointestinal adverse effects. Rebamipide suppresses gastric mucosal injury when administered with NSAIDs. This study aimed to determine rebamipide's influence upon renal effects following concomitant use with celecoxib or diclofenac. On day 0, rats were randomly divided into 6 groups (n≥6). On days 1 and 2, three groups received placebo and three groups were administered rebamipide (30mg/kg) twice daily. On day 3, the rats treated with placebo received another dose of placebo and ten minutes later a single dose of celecoxib (40mg/kg), diclofenac (10mg/kg), or placebo, respectively. The rats treated with rebamipide received one more dose of rebamipide and ten minutes later one single dose of celecoxib, diclofenac, or placebo, respectively. Urine and blood samples were collected on days 0, 2, and 3. Sodium and potassium excretion rates decreased significantly in the rats treated with celecoxib, diclofenac, rebamipide plus celecoxib, or rebamipide plus diclofenac on day 3. Blood urea nitrogen (BUN) levels significantly increased in placebo plus diclofenac and rebamipide plus diclofenac groups on day 3. Comparing the two groups, the levels of BUN was significantly higher in the rebamipide plus diclofenac group compared to that of placebo plus diclofenac group. Concomitant administration of rebamipide with either NSAID caused a rise in concentrations of urinary kidney injury molecule-1. Histopathological evaluations revealed an intensified NSAID-induced tubular necrosis by rebamipide. Based upon the results obtained, concomitant administration of rebamipide with NSAIDs enhances the effect of NSAIDs on tubular injury.European journal of pharmacology 11/2013; 720(1-3):138-46. DOI:10.1016/j.ejphar.2013.10.035 · 2.68 Impact Factor
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ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal and renal side effects. Rebamipide is a mucoprotective agent that reduces gastrointenstinal side effects when administered concomitantly with NSAIDs. In this study, we investigated the pharmacokinetic drug interactions of rebamipide with two selected NSAIDs, celecoxib or diclofenac. Rats were randomly divided into five groups. Two groups received placebo and three groups were administered rebamipide (30 mg/kg) orally twice daily for two days. On day 3, the animals treated with placebo received celecoxib (40 mg/kg) or diclofenac (10 mg/kg) and rats receiving rebamipide were administerd rebamipide followed by a single dose of placebo, celecoxib, or diclofenac. To investigate drug protein interactions, blank rat plasma was spiked with known concentrations of rebamipide, diclofenac plus rebamipide, or celecoxib plus rebamipide then dialyzed through a Rapid Equilibrium Dialysis device. AUC (139.70 ± 24.97 μg.hr/mL), Cmax (42.99 ± 2.98 μg/mL), and CLoral (0.08 ± 0.02 L/hr/kg) values of diclofenac in diclofenac plus rebamipide group altered when compared to those of diclofenac treated groups. Treatment with rebamipide showed no significant change in pharmacokinetic parameters of celecoxib treated rats. Cmax (7.80 ± 1.22 μg/mL), AUC (56.46 ± 7.30 μg.hr/mL), Vd/F (7.55 ± 1.37 L/kg), and CLoral (0.58 ± 0.09 L/hr/kg) of rebamipide were significantly altered when diclofenac was co-administered with rebamipide. Pharmacokinetic parameters of rebamipide plus celecoxib group were not significantly different from those of rebamipide group. Plasma protein binding was not affected by concomitant administration of another drug. These results indicate alteration of pharmacokinetic parameters of both rebamipide and diclofenac when co-administered and cannot be explained by a variation in plasma protein binding.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 12/2013; DOI:10.1016/j.ejps.2013.12.002 · 3.01 Impact Factor