RT Journal Article
SR Electronic
T1 Mechanism of Intestinal Absorption and Renal Reabsorption of an Orally Active Ace Inhibitor: Uptake and Transport of Fosinopril in Cell Cultures
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1307
OP 1315
VO 29
IS 10
A1 Cathaleen Shu
A1 Hong Shen
A1 Ulrich Hopfer
A1 David E. Smith
YR 2001
UL http://dmd.aspetjournals.org/content/29/10/1307.abstract
AB The objective of this study was to delineate the transepithelial transport mechanisms of fosinopril in cultured cell lines expressing the intestinal and renal peptide transporters. Lineweaver-Burk, Dixon, and dose-response analyses revealed that GlySar uptake was competitively inhibited by fosinopril in both Caco-2 (Ki, 35.5 μM) and SKPT cells (Ki, 29.6 μM). Intracellular accumulations of fosinopril were 3 to 4 times higher from apical versus basolateral surfaces of the membrane, as was the apical-to-basal flux of the drug. The apical peptide transporter had a significantly greater affinity for fosinopril than did the basolateral peptide transporter in Caco-2 cells (Km, 154 versus 458 μM, respectively;p < 0.001) and SKPT cells (Km, 22 versus 104 μM, respectively;p < 0.001). Moreover, fosinopril uptake by the basolateral peptide transporter was less sensitive to changes in medium pH than the apical peptide transporter in both cell lines. Although Caco-2 cells are known to express PEPT1 protein (and not PEPT2), our immunoblot analyses provide definitive evidence that SKPT cells express PEPT2 protein (and not PEPT1). Taken as a whole, our findings demonstrate that fosinopril is transported intact by PEPT2 and PEPT1, with high-affinity and by a proton-coupled, saturable process. Our results also suggest that distinct peptide transporters exist at the basolateral and apical membranes and that they play an important role in modulating the intestinal absorption and renal reabsorption of peptides and peptide-like drugs. The American Society for Pharmacology and Experimental Therapeutics