Differential Effects of Modified β‐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 β‐cyclodextrin (β‐CyD) or chemically modified β‐CyDs: 2,6‐di‐O‐methyl‐β‐CyD (DM‐β‐CyD), 2,3,6‐tri‐O‐methyl‐β‐CyD (TM‐β‐CyD) and 2‐hydroxypropyl‐β‐CyD (HP‐β‐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 β‐CyDs in the following order: DM‐β‐CyD > TM‐β‐CyD > HP‐β‐CyD > β‐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‐βCyD complex and halved for the others. BPAAA complexed with DM‐β‐CyD, HP‐β‐CyD or β‐CyD showed better gastric tolerability compared with uncomplexed drug, whereas the BPAA‐TM‐β‐CyD complex produced marked gastric lesions similar in extent to BPAA alone. TM‐β‐CyD (500mg kg−1) and DM‐β‐CyD (1000mg kg−1) caused gastric erosions 21 h after oral administration. The pharmacokinetic profiles of BPAA‐β‐CyD complexes have shown that DM‐β‐CyD is the most effective in enhancing the bioavailability of BPAA. 1995 Royal Pharmaceutical Society of Great Britain