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.

PURPOSE: To compare the intestinal absorption and active efflux protein 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 showed a distinct preference for transport in the basolateral to apical direction of Caco-2 monolayers as efflux was >20 times greater than apical to basolateral transport. Efflux of SDZ-RAD was completely inhibited by verapamil while efflux of rapamycin was mostly inhibited by verapamil 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 rapamycin 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. Rapamycin is also partially removed from cells by a second efflux system that is not responsive to SDZ-RAD. When these efflux pumps are inhibited SDZ-RAD is likely to be absorbed across the intestine at a faster rate than rapamycin.