Differential effects of modified beta-cyclodextrins on pharmacological activity and bioavailability of 4-biphenylacetic acid in rats after oral administration.
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.
Puglisi
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Instituto di Chimica Farmaceutica e Tossicologica, Università di Catania, Italy.
Ventura
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CA
Spadaro
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A
Campana
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Spampinato
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S
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000737:chemistry* / Q000378:metabolism; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems / Q000592:standards*; D016014:Linear Models; D008297:Male; D010648:Phenylacetates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship; D047392:beta-Cyclodextrins
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D010648:Phenylacetates; D047392:beta-Cyclodextrins; C012776:biphenylylacetic acid; C031215:betadex