Peptides and Related Drugs: A Review of Their Absorption, Metabolism, and Excretion

1 The somatostatin octapeptide-analogue, octreotide, is absorbed as intact peptide from the gastrointestinal (GI) tract. 2 In situ absorption experiments in rats confirmed our recent intubation studies in human volunteers demonstrating that the peptide has preferential absorption sites in the small intestine. Absorption of octreotide was higher in the jejunum than in the duodenum or the ileum. 3 Experiments with bile-duct cannulated rats demonstrated that the absorption of octreotide decreased in the presence of bile, reflecting a negative influence of biliary components on the absorption of the peptide. 4 Uptake experiments using rat jejunal brush border membranes were performed to analyse the absorption mechanisms. The transport of octreotide into jejunal brush border membranes was significantly higher than the uptake into membrane vesicles isolated from rat ileum. When initial uptake (0-15 s) rates into the membrane vesicles were calculated as a function of the peptide concentration, a saturable component could be observed, indicative of transport mechanisms different from simple diffusion.

Section: Discussioncontrasting

confidence: 49%

Enteral absorption of octreotide

Fricker

Drewe

Vonderscher

et al. 1992

“…Surprisingly high levels of oral bioavailability are observed with peptide-like drugs (Humphrey, 1986;Humphrey & Ringrose, 1986). Some /-lactam antibiotics (cefadroxil and cephalexin) and angiotensin converting enzyme (ACE) inhibitors (enalapril maleate and captropril) are now known to be effective substrates for the H + /ditripeptide transporter present in the apical membrane of intestinal enterocytes (Fei et al, 1994;Boll et al, 1994;Thwaites et al, 1994a).…”

Section: Discussionmentioning

confidence: 99%

D‐Cycloserine transport in human intestinal epithelial (Caco‐2) cells: mediation by a H ⁺ ‐coupled amino acid transporter

Thwaites

Armstrong

Hirst

et al. 1995

Medical School, Newcastle upon Tyne, NE2 4HH1 The ability of D-cycloserine to act as a substrate for H+/amino acid symport has been tested in epithelial layers of Caco-2 human intestinal cells. 2 In Na+-free media with the apical bathing media held at pH 6.0, D-cycloserine (20 mM) is an effective inhibitor of net transepithelial transport (Jnet) of L-alanine (100 pM) and its accumulation (across the apical membrane) in a similar manner to amino acid substrates (L-alanine, /3-alanine, L-proline and glycine). In contrast L-valine was ineffective as an inhibitor for H'/amino acid symport. Both inhibition of L-alanine Jne, and its accumulation by D-cycloserine were dose-dependent, maximal inhibition being achieved by 5-10 mM. 3 Both D-cycloserine and known substrates for H+/amino acid symport stimulated an inward short circuit current (ISC) when voltage-clamped monolayers of Caco-2 epithelia, mounted in Ussing chambers, were exposed to apical substrate in Na+-free media, with apical pH held at 6.0. The D-cycloserine dependent increase in ISC was dose-dependent with an apparent Km = 15.8 + 2.0 (mean + s.e.mean) mm, and Vma,, = 373 + 21 nmol cm-2 h-'. 4 D-Cycloserine (20 mM) induced a prompt acidification of Caco-2 cell cytosol when superfused at the apical surface in both Na+ and Na+-free conditions. Cytosolic acidification in response to D-cycloserine was dependent upon superfusate pH, being attenuated at pH 8 and enhanced in acidic media. 5 The increment in ISC with 20 mM D-cycloserine was non-additive with other amino acid substrates for H+/amino acid symport.

“…Results are expressed as mean ± s.e.mean (n = 7-11); ***P < 0.001; **P < 0.05; NSP< 0.05 versus control data. Oral bioavailability is crucial to the use of angiotensinconverting enzyme (ACE) inhibitors in the clinical treatment of systemic hypertension and congestive heart failure (Humphrey, 1986;Humphrey & Ringrose, 1986). Captopril demonstrates high oral bioavailability (62%) in man with a peak plasma concentration after 1 h (Duchin et al, 1982).…”

Section: Resultsmentioning

confidence: 99%

“…The specificity of this cloned H+-coupled transporter is similar to the specificity of the H+-coupled di/tripeptide carrier in the human intestine epithelial cell line Caco-2 (Thwaites et al, 1994a). Although the gastrointestinal epithelial cell wall represents a major barrier to drug delivery via the oral route, many peptide-like drugs have significant oral bioavailability (Humphrey, 1986;Humphrey & Ringrose, 1986). 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.…”

Section: Introductionmentioning

confidence: 96%

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

Thwaites

Cavet

Hirst

et al. 1995

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.