Decreased bioavailability of carbamazepine suppository after its intrarectal and intracolostomal administration to rectal-resected or colostoma-constructed rabbits

Abstract

The pharmacokinetics of carbamazepine (CBZ), one of the useful analgesic adjunctive agents for palliative care, and its major active metabolite, CBZ-10,11-epoxide (CBZ-E), were investigated after the intrarectal and intracolostomal administration of CBZ to rabbits with rectal-resection or colostoma-construction. In rectal-resected rabbits, the bioavailability of CBZ and the plasma level of CBZ-E after rectal administration were significantly lower than those in normal rabbits, and furthermore these values after intracolostomal administration to colostoma-constructed rabbits tended to be lower than those in rectal-resected ones. This decreased bioavailability of CBZ was thought to be not due to an increased first-pass effect, but to the lower CBZ absorption ability in the upper rectum and colon, since absorption profile of CBZ was not affected by first-pass metabolism. When the dose was increased based upon the difference in the absolute bioavailability values in the rectal-resected and colostoma-constructed rabbits, the decreased plasma levels of CBZ were restored to the control levels incompletely, and the elimination of CBZ and CBZ-E was retarded. These findings suggest that owing to the similarity of their pharmacokinetics in rabbit and man, the increment of dosages of CBZ should be avoided, when CBZ suppositories are administered to rectal-resected or colostoma-constructed patients.