INCLUSION COMPLEXATION OF AMIDE-TYPED LOCAL-ANESTHETICS WITH BETA-CYCLODEXTRIN AND ITS DERIVATIVES - III - BIOPHARMACEUTICS OF BUPIVACAINE-SBE7-BETA-CD COMPLEX FOLLOWING PERCUTANEOUS SCIATIC-NERVE ADMINISTRATION IN RABBITS

The effect of a new modified beta-cyclodextrin derivative, sulfobutyle ther7-beta-cyclodextrin (SBE7-beta CD) on the biopharmaceutics of loca l anesthetic bupivacaine (BVC) was studied in a rabbit sciatic model. Phase-solubility study revealed the formation of a 1:1 complex of the Al type between BVC and SBE7-beta CD, with an apparent stability const ant of 149 +/- 7 M-1. Then, BVC hydrochloride (BVC-HCl) and BVC comple xed with SBE7-beta CD (BVC-SBE7-beta CD) Were administered around the sciatic nerve both as solutions, in a randomized cross-over design in six New Zealand rabbits. The plasma concentrations of BVC, the onset a nd duration of motor blockade were evaluated. For the dose of BVC inje cted (5 mg in 2.5 ml), complexation with SBE7-beta CD led to a decreas e in the maximum plasma concentration (C-max) of BVC, while the time t o reach C-max (T-max) was increased. Complexation also delayed the ons et of motor block and did not modify its duration. This decrease in ab sorption rate of BVC following complex administration was confirmed by Loo-Riegleman absorption analysis. The effect of SBE7-beta CD concern ed mainly the faster absorption phase, responsible for side effects, b ut had also an impact on the slower phase, even if not stastistically significant, shown by a flip-flop in the elimination constant. Complex ation may be useful to improve the therapeutic index of local anesthet ics, allowing greater amounts of drug to be injected in order to prolo ng nerve blockade. (C) 1998 Elsevier Science B.V. All rights reserved.