Kinetics and mechanism of uptake of platinum-based pharmaceuticals by the rat small intestine.
The absorption of two platinum-based pharmaceuticals, cisplatin and carboplatin, was studied using in vitro and in situ models. By utilizing everted rat small intestine, it was found that absorption of both drugs was linear with time up to 60 min and was not saturable up to a concentration of 1.0 mM. Moreover, uptake against a concentration gradient could not be demonstrated and absorption was not reduced by metabolic inhibition or anoxic conditions. These results indicate the lack of involvement of an active transport mechanism for cisplatin and carboplatin and imply that absorption across the gastrointestinal tract is by passive diffusion. Cisplatin was absorbed more readily than carboplatin, both in vitro and in situ. In situ both drugs were found to disappear from the intestinal lumen following first-order kinetics. The results of in situ studies indicate that a decrease in pH of the perfusion medium leads to an increase in absorption of carboplatin into the systemic blood. This report establishes the fact that both cisplatin and carboplatin are absorbed across the gastro-intestinal tract and indicates that preclinical trials involving oral administration of platinum-based pharmaceuticals could be justified.
Binks
S P
SP
Institute of Occupational Health, University of Birmingham, U.K.
Dobrota
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D016190:Carboplatin; D002945:Cisplatin / Q000493:pharmacokinetics*; D003486:Cyanides / Q000494:pharmacology; D006207:Half-Life; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009584:Nitrogen / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics*; D010984:Platinum / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D003486:Cyanides; D009944:Organoplatinum Compounds; D010984:Platinum; D016190:Carboplatin; D009584:Nitrogen; D002945:Cisplatin