Combination effects of alpha-cyclodextrin and xanthan gum on rectal absorption and metabolism of morphine from hollow-type suppositories in rabbits.

Pharmacokinetics of morphine and its glucuronides in plasma were studied after rectal administration of hollow-type oleaginous suppositories containing kneading mixtures of morphine hydrochloride, alpha-cyclodextrin, and/or xanthan gum in rabbits. In combination with xanthan gum, alpha-cyclodextrin reduced the first-pass metabolism of morphine in the rectal mucosa and by the liver and improved the apparent rectal bioavailability of the opioid about 4 fold. In vitro permeation studies using an isolated rectal mucosal preparation of rabbits revealed that alpha-cyclodextrin increased the transepithelial conductance and facilitated the transport of morphine through the rectal mucosa. Furthermore, alpha-cyclodextrin facilitated its own mucosal permeation and reduced the glucuronidation of morphine during the passage through the rectal mucosa, probably through restricting the formation of a catalytic complex of morphine with glucuronyltransferases, rather than because of the enzyme saturation. The present data suggest that alpha-cyclodextrin in combination with xanthan gum is particularly effective in improving the rectal bioavailability of morphine from hollow-type suppositories.