The intestinal absorption mechanism of two nonsulfhydril lysyl-proline angiotensin converting enzyme (ACE) inhibitors, lisinopril (1) and SQ 29,852 (2; [(S)-1-[6-amino-2-[hydroxy(4-phenylbutyl)-phosphinyl]oxy]-1 -oxohexyl]-L -proline) were investigated in rats using a single-pass perfusion method. Compound 2 is well absorbed from rat jejunum, whereas lisinopril absorption is relatively low. The permeability of both ACE inhibitors is concentration dependent and is decreased by the dipeptide Tyr-Gly and by cephradine, indicating a nonpassive absorption mechanism via the peptide carrier-mediated transport system. Compound 2 is well absorbed by a nonpassive mechanism, in parallel with a small passive component. The estimated dimensionless carrier parameters for 2 are Jmax = 0.16, Km = 0.08 mM, Pc = 2.0, and Pm = 0.25; for lisinopril, passive absorption is not significant and its absorption is nonpassive: Jmax = 0.032, Km = 0.082 mM, and Pc = 0.39 (where Jmax is the maximal flux, Km is the Michaelis constant, Pc is the carrier permeability, and Pm is the passive permeability). These results offer a mechanistic explanation for the prolonged ACE inhibition and the low oral bioavailability of lisinopril, and for the nonlinear pharmacokinetics of 2.