Characterization of mitomycin C-induced gastrointestinal damage. I. In situ recirculation experiment.
The effects of mitomycin C (MMC), an anti-tumor agent, on the intestinal absorption of various drugs in rats were investigated. Based on microscopic observations, preadministration of a single intravenous dose of MMC (3 mg/kg) caused serious degeneration of epithelial cells, villous atrophy, and mitotic arrest in crypts at 48 hr after pretreatment. At this time point, absorption of sulfanilamide, salicylic acid, cephalexin, and L-tryptophan was shown to be significantly decreased by means of an in situ recirculation technique. The histological changes and the decrease in absorption of sulfanilamide, a model for passively absorbed drugs, were shown to depend on the timing of MMC pretreatment. Maximal effects were observed 48 hr after dosing. The MMC-induced reduction in the absorption of drugs was not a result of differences between treated and control animals with respect to pH of the drug solution, binding of drugs with intraluminal macromolecules, or intestinal mucosal blood flow. The absorption of sulfanilamide from the small intestine in the in situ system correlated well with the wet weight of the small intestine regardless of pretreatment dose or route. This suggests that the change in absorptive surface area of the intestinal mucosa may play a major role in the MMC-induced decrease in absorption capacity of the intestine.
Mizuno
M
M
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Kawabata
S
S
Hamaura
T
T
Hashida
M
M
Sezaki
H
H
D000818:Animals; D004305:Dose-Response Relationship, Drug; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D016685:Mitomycin; D008937:Mitomycins / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013449:Sulfonamides / Q000493:pharmacokinetics
D008937:Mitomycins; D013449:Sulfonamides; D016685:Mitomycin