Role of the monocarboxylic acid transport system in the intestinal absorption of an orally active beta-lactam prodrug: carindacillin as a model.
Transport of carbenicillin (CBPC) and its orally active prodrug (carindacillin, CIPC) was studied with rat intestinal brush border membrane vesicles (BBMV). CIPC was transported uphill into BBMV in the presence of a H(+) gradient, indicating that CIPC absorption is carrier-mediated. Indeed, CIPC was predominantly transported by the monocarboxylic acid transport system, although it might be possible that CIPC possesses some affinity to the oligopeptide transporter. In contrast, CBPC exhibited no affinity to either the oligopeptide or the monocarboxylic acid transport system. Apparent uptake clearance of CIPC was approximately 70-fold greater than that of CBPC. It was clarified that the modification of the chemical structure of CBPC (a dicarboxylic acid) to CIPC (a monocarboxylic acid) by ester formation may have resulted in the increased affinity to the monocarboxylic acid transport system, which, in turn, led to improved absorption of the prodrug.
Li
Y H
YH
School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, Japan.
Tanno
M
M
Itoh
T
T
Yamada
H
H
D000465:Algorithms; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D001693:Biological Transport, Active / Q000502:physiology; D002228:Carbenicillin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000502:physiology*; D007583:Jejunum / Q000378:metabolism; D008871:Microvilli / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats
D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D011355:Prodrugs; C100244:carbenicillin indanyl; D002228:Carbenicillin