biphenylylacetic-acid and Stomach-Ulcer

Gastric tolerability, absorption and pharmacological activity of the non-steroidal anti-inflammatory drug 4-biphenylacetic acid (BPAA), as an inclusion complex with beta-cyclodextrin (beta-CyD) or chemically modified beta-CyDs: 2,6-di-O-methyl-beta-CyD (DM-beta-CyD), 2,3,6-tri-O-methyl-beta-CyD (TM-beta-CyD) and 2-hydroxypropyl-beta-CyD (HP-beta-CyD), were investigated in the rat after oral administration. BPAA absorption, determined from area under the plasma concentration-time curve (AUC), was increased by complexation with all beta-CyDs in the following order: DM-beta-CyD > TM-beta-CyD > HP-beta-CyD > beta-CyD. The carrageenan paw oedema test demonstrated a significant increase in anti-inflammatory activity of BPAA and the ED50 values, compared with BPAA alone, were reduced to about a third for the BPAA-DM-beta-CyD complex and halved for the others. BPAA complexed with DM-beta-CyD, HP-beta-CyD or beta-CyD showed better gastric tolerability compared with uncomplexed drug, whereas the BPAA-TM-beta-CyD complex produced marked gastric lesions similar in extent to BPAA alone. TM-beta-CyD (500 mg kg-1) and DM-beta-CyD (1000 mg kg-1) caused gastric erosions 21 h after oral administration. The pharmacokinetic profiles of BPAA-beta-CyD complexes have shown that DM-beta-CyD is the most effective in enhancing the bioavailability of BPAA.

Topics: Absorption; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Biological Availability; Chromatography, High Pressure Liquid; Cyclodextrins; Delayed-Action Preparations; Drug Delivery Systems; Linear Models; Male; Phenylacetates; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Structure-Activity Relationship

4-Biphenylacetic acid, a potent non-steroidal anti-inflammatory agent forms a solid inclusion complex with beta-cyclodextrin in a 1:1 molar ratio, which exhibits better solubility and dissolution characteristics than the uncomplexed drug. Following oral administration of the complex to rats, quicker and higher drug plasma concentrations can be achieved than with the drug alone. Parallel studies, using the carrageenan paw oedema test, demonstrate a greater anti-inflammatory activity of the complex (ED50 of 2.9 mg kg-1 for the complex and of 6.2 mg kg-1 for the free drug). The complex displayed a better gastric tolerability in the rat than drug alone.

Topics: Administration, Oral; Animals; beta-Cyclodextrins; Biological Availability; Carrageenan; Cyclodextrins; Edema; Male; Phenylacetates; Rats; Rats, Inbred Strains; Stomach Ulcer