Angiotensin converting enzyme inhibitors transporters

Human PepTl was initially cloned from intestine (92) and was found to be localized to the brush border of intestinal epithelial cells (93) and in SI segment of apical proximal tubules (94). PepTl transports (3-lactam antibiotics (95), antiviral drugs such as valacyclovir and valganciclovir (96), and the angiotensin converting enzyme inhibitor captopril (97). Polymorphisms have been reported, however little is known regarding their functional consequences (64). 

The angiotensin-converting enzyme inhibitors, quinapril and enalapril, have affinity for the peptide transporters, however it is not known whether they are transported. 

Other important renal transport systems include the peptide transporters, which are involved in the uptake of peptide-like drugs including /3 -lactam antibiotics and angiotensin-converting enzyme inhibitors, and nucleoside transporter proteins, which are involved in uptake of nucleosides and nucleoside analogs (e.g., zidovudine and dideoxyinosine). ... 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

For compounds not metabolized by the gut wall, liver, or affected by transporters, a direct relationship between oral absorption and bioavailability should be observed. The calculated oral absorption, using PSA as a measure for passive membrane permeability reflecting the absorption step, relates to the in vivo observed bioavailability for three classes of compounds - angiotensin-converting enzymes (ACE) inhibitors, P-blockers, and calcium antagonists - is shown below [25],... 

Intestinal absorption of beta-lactams occurs at least in part by an active mechanism involving a dipeptide carrier, and this pathway can result in interactions with dipeptides and tripeptides (196,197), which reduce the rate of absorption of the beta-lactams. In particular, angiotensin-converting enzyme (ACE) inhibitors, which have an oligopeptide structure, are absorbed by the same carrier (198) and interact with beta-lactams in isolated rat intestine (199). However, there might be a second site of interaction between ACE inhibitors and beta-lactams. Both groups of substances are excreted by the renal anionic transport system, and concomitant administration of both drugs sometimes results in pronounced inhibition of the elimination of beta-lactams (200). In the case of cefalexin, it may not lead to toxic effects. However, when more toxic beta-lactams are used, the possibility of this interaction has to be kept in mind. 

Thwaites DT, Cavet M, Hirst BH, and Simmons NL (1995) Angiotensin-converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco-2) cells. Br J Pharmacol 114 981-986. 

---