Uptake of prodrugs by rat intestinal mucosal cells: mechanism and pharmaceutical implications

The in vitro intestinal ring uptake of prednisolone (11 beta,17,21-trihydroxypregna-1,4-diene-3,20-dione), prednisolone 21-succinate, and prednisolone 21-phosphate was compared in rings prepared from rat jejunum and colon. An HPLC assay was developed to determine whether the drug or intact prodrug was taken up by the tissue. In jejunum and colon, the uptake of prednisolone was limited by its solubility (0.84 mM, 37 degrees C). The freely soluble succinate and phosphate esters were well absorbed in the jejunum. The only species detected in jejunal tissue after incubation with prednisolone 21-phosphate was prednisolone, indicating hydrolysis prior to absorption. This implication was verified by light microscopy. Incubation of tissue from the jejunum with prednisolone 21-succinate resulted in uptake of a mixture of prodrug and parent drug, with the latter form predominating. Prednisolone 21-succinate was also absorbed well in the colon, where the predominant species taken up by the tissue was the intact ester. The half-life of the succinate ester in the tissue was approximately 1 h postincubation, implicating enzyme mediation. Uptake of the phosphate ester by the colon was less than 20% of that observed in the jejunum, with the species absorbed still being primarily the parent alcohol. Light microscopy techniques confirmed that prednisolone 21-phosphate and hydrocortisone 21-phosphate are good substrates for brush border membrane alkaline phosphatase in the jejunum, and that lack of this enzyme in colon tissue was most likely responsible for poor uptake in the colon.