Diflunisal disposition. Role of gastric absorption in the development of mucosal damage and anti-inflammatory potency in rodents.
Aspirin shows a high incidence of gastric side effects. These are thought to result from both systemic and local effects during drug absorption. In contrast, a lipophilic derivative of salicylic acid, diflunisal, causes significantly fewer adverse gastric effects. This is thought to be due to a lack of gastric absorption. To test this hypothesis, three types of experiments were performed with diflunisal: 1. Transgastric permeation was quantified under different pH conditions, using an isolated mouse stomach model. 2. Ulcerogenic potencies of buffered and unbuffered drug solutions were determined in rats. 3. The time course of its anti-inflammatory effect and the serum concentrations of diflunisal, given alone and with neutralizing buffer, were measured in rats with carrageenan-induced paw edema. Corresponding to the low gastric ulcerogenicity, absorption of diflunisal in the isolated stomach preparations was very small. However, absorption was pH-dependent and ranged between 0.69 and 8.73% with a maximum at pH 4.5. Gastric lesions were found to be more evident 24 hr after drug administration than after 5 hr. Comparing buffered vs. unbuffered diflunisal preparations, no difference in ulcerogenicity was detectable. However, using a buffered preparation, the anti-inflammatory effect of diflunisal was enhanced significantly (p less than 0.01), and elevated serum concentrations were found (p less than 0.05). The results show that raising the solubility of diflunisal does not influence gastric absorption or gastric toxicity considerably. However, its serum concentrations and systemic anti-inflammatory effects were significantly enhanced.
Nuernberg
B
B
Institute of Pharmacology and Toxicology, University of Erlangen-Nurenberg.
Szelenyi
I
I
Schneider
H T
HT
Brune
K
K
D000042:Absorption; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002351:Carrageenan; D004058:Diffusion; D004061:Diflunisal / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005745:Gastric Acidity Determination; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004061:Diflunisal; D002351:Carrageenan