IN-VITRO AND IN-SITU ABSORPTION OF SDZ-RAD USING A HUMAN INTESTINAL-CELL LINE (CACO-2) AND A SINGLE-PASS PERFUSION MODEL IN RATS - COMPARISON WITH RAPAMYCIN

Authors
Citation
A. Crowe et M. Lemaire, IN-VITRO AND IN-SITU ABSORPTION OF SDZ-RAD USING A HUMAN INTESTINAL-CELL LINE (CACO-2) AND A SINGLE-PASS PERFUSION MODEL IN RATS - COMPARISON WITH RAPAMYCIN, Pharmaceutical research, 15(11), 1998, pp. 1666-1672
Citations number
28
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Pharmacy",Chemistry
Journal title
ISSN journal
0724-8741
Volume
15
Issue
11
Year of publication
1998
Pages
1666 - 1672
Database
ISI
SICI code
0724-8741(1998)15:11<1666:IAIAOS>2.0.ZU;2-7
Abstract
Purpose. To compare the intestinal absorption and active efflux protei n susceptibility of a new immunosuppressive agent (SDZ-RAD) with that of its analog rapamycin. Methods. Caco-2 cell monolayers were used to examine bidirectional transport of the two compounds at low micromolar concentrations. Single pass rat intestinal perfusion was also used to examine steady state permeability. Results. Rapamycin and SDZ-RAD sho wed a distinct preference for transport in the basolateral to apical d irection of Caco-2 monolayers as efflux was >20 times greater than api cal to basolateral transport. Efflux of SDZ-RAD was completely inhibit ed by verapamil while efflux of rapamycin was mostly inhibited by vera pamil and partially inhibited by probenecid. Passive permeability was shown to be 20 x 10(-6) cm/sec for SDZ-RAD and 10 x 10(-6) cm/sec for rapamycin. In situ rat studies also showed the permeability of rapamyc in to be half that of SDZ-RAD with permeabilities of 12.6 x 10(-6) for rapamycin and 24.8 x 10(-6) cm/sec for SDZ-RAD. Conclusions. SDZ-RAD and rapamycin are strong substrates for P-gp-like mediated efflux. Rap amycin is also partially removed from cells by a second efflux system that is not responsive to SDZ-RAD. When these efflux pumps are inhibit ed SDZ-RAD is likely to be absorbed across the intestine at a faster r ate than rapamycin.