Uptake and transport of the ACE-inhibitor ceronapril (SQ 29852) by monolayers of human intestinal absorptive (Caco-2) cells in vitro

The angiotensin-converting enzyme (ACE)-inhibitor ceronapril (SQ 29852) is shown to be a substrate of the intestinal dipeptide transporter. Uptake by Caco-2 cells, grown as confluent monolayers, follows a major saturable pathway (K-m, 0.91 +/- 0.11 mM; similar to 90% at 1 mM) together with a minor passive component (k(d), 32.3 +/- 6.6 ng (10(6) cells)(-1) (20 min)(-1). Uptake was inhibited by competition with dipeptides such as L-Ala-L-Pro (K-i, 2.96 mM) and L-Phe-Gly (K-i, 3.84 mM) but not by cephalosporins such as cephalexin. In contrast, transport was non-saturable, flux increased linearly with concentration and data were consistent with a passive transepithelial transport mechanism. Transport profiles showed a biphasic dependence upon time with an initial flux of 0.83 +/- 0.02 ng insert(-1) min(-1) (k(I)) and a terminal value of 1.65 +/- 0.08 ng insert(-1) min(-1) (k(2)) at 100 mu M. It is concluded that the basolateral efflux is retarded so that the passive paracellular transport controls the overall transepithelial transport characteristics in the Caco-2 model. Carrier-mediated uptake into intestinal enterocytres, followed by rate-limiting basolateral efflux, may explain the extended t(max) in vivo following oral administration.