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.
Kondo
T
T
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Irie
T
T
Uekama
K
K
D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D003505:Cyclodextrins / Q000008:administration & dosage*; D004337:Drug Carriers; D005965:Glucuronates / Q000378:metabolism; D007408:Intestinal Absorption; D008297:Male; D009020:Morphine / Q000493:pharmacokinetics*; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage*; D011817:Rabbits; D012007:Rectum / Q000378:metabolism*; D013488:Suppositories; D047391:alpha-Cyclodextrins
D000701:Analgesics, Opioid; D003505:Cyclodextrins; D004337:Drug Carriers; D005965:Glucuronates; D011135:Polysaccharides, Bacterial; D013488:Suppositories; D047391:alpha-Cyclodextrins; D009020:Morphine; C002563:xanthan gum; C032613:alpha-cyclodextrin