Oral bioavailability and hypoglycaemic activity of tolbutamide/cyclodextrin inclusion complexes

The purpose of the present study was to evaluate the enhancement of tolbuta mide (TBM) oral bioavailability and hypoglycaemic activity through complexa tion with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin ( HP-beta-CD). TBM and its freeze-dried inclusion complexes were administered to rabbits (New zealand breed; n = 6), in a dose of 20 mg/kg. TMB plasma l evels were measured by HPLC and glucose levels were analysed according to T rinder (Trinder, P., 1969. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann. Clin. Biochem. 6, 24=28). The pure drug attained a maximum of plasma concentration (C-max) of 18.58 +/- 3.27 mu g/ml at 8.5 h (T-max), whereas with inclusion complexes, C-max increased about two times and appeared at ca. 4 h. AUC(0) (24) of complexes was about 1.6 times as much as that of the pure drug. Thus, the extent of oral absorption of TBM from inclusion complexes was significantly greater a nd faster when compared with drug alone, in addition, without cyclodextrins the maximum hypoglycaemic effect (CVG(max)) of TBM (34.1%) was observed at 5.6 h (Tg(max)). CVG(max) of TBM/beta-CD and TBM/HP-beta-CD inclusion comp lexes were 34.1% (at 6.5 h) and 37.7% (at 5.1 h), respectively. AAC(0-24) o f inclusion complexes was 1.4 times larger than that of pure drug. Hence, t he oral administration of complexed TBM not only improved the drug absorpti on, but also the TBM hypoglycaemic activity. (C) 2000 Elsevier Science B.V. All rights reserved.