Intestinal Absorption Mechanism of Dipeptide Angiotensin Converting Enzyme Inhibitors of the Lysyl-Proline Type: Lisinopril and SQ 29,852

Friedman, Doron; Amidon, Gordon L.

doi:10.1002/jps.2600781205

Cited by 73 publications

(38 citation statements)

References 7 publications

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“…A passive mechanism of lisinopril absorption is consistent with the slow rate of disappearance observed in the experiments with rat jejunum (Friedman & Amidon, 1989b) and in studies in man .…”

Section: Resultssupporting

confidence: 86%

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Angiotensin‐converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco‐2) cells

Thwaites

Cavet

Hirst

et al. 1995

British J Pharmacology

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1 The role of proton-linked solute transport in the absorption of the angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril maleate and lisinopril has been investigated in human intestinal epithelial (Caco-2) cell monolayers. 2 In Caco-2 cell monolayers the transepithelial apical-to-basal transport and intracellular accumulation (across the apical membrane) of the hydrolysis-resistant dipeptide, glycylsarcosine (Gly-Sar), were stimulated by acidification (pH 6.0) of the apical environment. In contrast, transport and intracellular accumulation of the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, were low (lower than the paracellular marker mannitol) and were not stimulated by apical acidification.

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Section: Resultssupporting

confidence: 86%

“…The H+-coupled dipeptide carrier may play an important role in the oral absorption of a number of these peptide-like drugs including the angiotensin-converting ' Author for correspondence. enzyme (ACE) inhibitors, enalapril (Friedman & Amidon, 1989a), captopril (Hu & Amidon, 1988) and lisinopril (Friedman & Amidon, 1989b).…”

Section: Introductionmentioning

confidence: 99%

Angiotensin‐converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco‐2) cells

Thwaites

Cavet

Hirst

et al. 1995

British J Pharmacology

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“…Examples of drugs and prodrugs that act as substrates for PepT1 include b-lactam antibiotics, cephalosporins, ACE-inhibitors, L-valine ester prodrugs such as valacyclovir, renin and thrombin inhibitors, bestatin, and the valine ester prodrugs of aciclovir and ganciclovir. [88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106] It would be interesting to investigate hPepT1-mediated transport of anti-inflammatory di-and tripeptides. For example, the tripeptide KPV was recently shown to have antiinflammatory activities.…”

Section: Perspectivesmentioning

confidence: 99%

The oligopeptide transporter hPepT1: gateway to the innate immune response

Charrier

Merlin

2006

Laboratory Investigation

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Bacterial products that are normally present in the lumen of the colon, such as N-formylated peptides and muramyl-dipeptide, are important for inducing the development of mucosal inflammation. The intestinal dipeptide transporter, hPepT1, which is expressed in inflamed but not in noninflamed colonic epithelial cells, mediates the transport of these bacterial products into the cytosol of colonic epithelial cells. The small bacterial peptides subsequently induce an inflammatory response, including the induction of MHC class I molecules expression and cytokines secretion, via the activation of nucleotide-binding site and leucine-rich repeat (NBS-LRR) proteins, for example NOD2, and activation of NF-jB. Subsequent secretion of chemoattractants by colonic epithelial cells induces the movement of neutrophils through the underlying matrix, as well as across the epithelium. These bacterial products can also reach the lamina propria through the paracellular pathway and across the basolateral membrane of epithelial cells. As a consequence, small formylated peptides can interact directly with immune cells through specific membrane receptors. Since immune cells, including macrophages, also express hPepT1, they can transport small bacterial peptides into the cytosol where these may interact with the NBS-LRR family of intracellular receptors. As in intestinal epithelial cells, the presence of these small bacterial peptides in immune cells may trigger immune response activation.

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“…While the association we studied has limited therapeutic or toxic consequences (the higher cefixime concentrations with nifedipine are probably not toxic and may be more effective), the interaction observed with the dipeptide transport system should be taken into account when nifedipine is given simultaneously with other drugs known to be absorbed by the same mechanism, for example, some converting-enzyme inhibitors (5). Moreover, these data may be of help in the …”

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confidence: 99%

Modification of cefixime bioavailability by nifedipine in humans: involvement of the dipeptide carrier system

Duverne

Bouten

Deslandes

et al. 1992

Antimicrob Agents Chemother

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We studied the action of nifedipine on the bioavailablity of cefixime, a molecule absorbed via the gut wall dipeptide carrier system in the rat, and on the bioavailability of D-xylose, which is absorbed via a pH (and Na+-)-dependent transporter. Each compound was administered alone or in combination with 20 mg of nifedipine to eight healthy male volunteers. Nifedipine significantly increased the absorption rate of cefixime (20.7 + 4.3 versus 16 ± 3.5 mg/h in the absence of nifedipine). The absolute bioavailability of cefixime alone was 31% ± 6% compared with 53% ± 1% (P < 0.01) in the presence of nifedipine. The observed peak concentrations in serum were significantly different (2.5 ± 0.3 mg/liter without nifedipine and 3.7 ± 1.1 mg/liter with nifedipine; P < 0.02). In contrast, nifedipine induced no significant differences in the pharmacokinetic profile of xylose following oral administration. We conclude that (i) cefixime is absorbed in humans by an apparently active process which can be enhanced by a calcium channel blocker, in this case, nifedipine; and (ii) nifedipine does not modify the activity of the pentose transporter.Cefixime was the first broad-spectrum oral cephalosporin to be marketed. It is characterized by the presence of two nonesterified carboxylic functions and by its stability to acid hydrolysis, which is due to the presence of a vinyl group on the cephem nucleus (12).Intestinal absorption of cefixime in the rat occurs by an active mechanism involving a pH-dependent dipeptide transporter similar to that of amoxicillin (14-16). The transporter is saturable and is inhibited by glycyl-L-proline and glycyl-L-glycine. The same mechanism has been hypothesized by Lowther et al. (9), who studied human brush border membrane vesicles. Recent studies in healthy volunteers have shown that nifedipine increases both the absorption rate and the bioavailability of amoxicillin without modifying its distribution or elimination (18). This may be explained by a direct stimulation of drug uptake, as the decrease in intracellular calcium levels increases transmembrane Na+-H+ ion exchanges, resulting in increased intraenterocyte pH, which in turn increases the activity of the transporter (18).Since animal studies have shown that the transport systems for cefixime and amoxicillin are the same (15), we assessed the absorption rate of cefixime and the influence of nifedipine on the intestinal absorption kinetics and bioavailability of cefixime in healthy volunteers.In order to identify the specificity of the interaction, we studied the action of nifedipine on the uptake of a pentose (D-xylose), which, when administered at the dose of 5 g, is absorbed via a pH (and Na+-)-dependent transporter (4,8 Protocol. The protocol was divided into two phases, cefixime-nifedipine and D-xylose-nifedipine, and the same subjects were used in both.(i) Phase 1: cefixime-nifedipine. The protocol for phase 1 was similar to that used by Westphal et al. (18) and involved oral administration followed by i.v. administration. In the study of ...

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Intestinal Absorption Mechanism of Dipeptide Angiotensin Converting Enzyme Inhibitors of the Lysyl-Proline Type: Lisinopril and SQ 29,852

Cited by 73 publications

References 7 publications

Angiotensin‐converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco‐2) cells

Angiotensin‐converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco‐2) cells

The oligopeptide transporter hPepT1: gateway to the innate immune response

Modification of cefixime bioavailability by nifedipine in humans: involvement of the dipeptide carrier system

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