The Oral Bioavailability of Peptides and Related Drugs

Humphrey, Michael

doi:10.1007/978-1-4757-9960-6_11

Cited by 26 publications

(23 citation statements)

References 36 publications

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“…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

British J Pharmacology

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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.

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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

British J Pharmacology

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“…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: 68%

“…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%

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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“…In addition, peptides and proteins exhibit a low permeability across the gastrointestinal mucosa because they are hydrophilic and have a high molecular weight (1)(2)(3)(4)(5). For orally administered peptides and proteins to reach their site of action, they must be able to resist chemical and enzymatic degradation in the gut lumen and then, after penetration of the mucosal membranes, to escape first -pass metabolism and clearance by the intestinal mucosa and liver.…”

Section: Gastrointestinal Transportmentioning

confidence: 99%

“…In addition to the enzymatic barriers, the intestinal absorption of peptide and protein drugs is severely hampered by physical barriers as represented by the mucous layer, the intestinal epithelial cell membranes, and the tight junctions between the apical ends of the epithelial cells (1,9,10). The epithelial cells of the entire intestine are covered by a mucous layer, consisting of water, mucins (glycoproteins), electrolytes, proteins and nucleic acids.…”

Section: Table IImentioning

confidence: 99%

Transport of peptide and protein drugs across biological membranes

Verhoef¹,

Boddé²,

Boer³

et al. 1990

Eur. J. Drug Metab. Pharmacokinet.

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The transport characteristics of peptide and proteins drugs across various epithelial membrane barriers are outlines. These include transport through the intestinal, buccal, nasal and pulmonary absorptive mucosae, as well as transdermal penetration. Because peptides and proteins are hydrophilic and high molecular weight compounds, they commonly show minor permeability across the mentioned biological membranes. In order to improve their transport properties and thereby their systemic bioavailability, several strategies can be undertaken, such as the synthesis of stabilized and lipophilic analogues, the application of absorption enhancers and protease inhibitors, and the design of suitable dosage forms (e.g., liposomes, biodegradable nanocapsules, bioadhesive microspheres).

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The Oral Bioavailability of Peptides and Related Drugs

Cited by 26 publications

References 36 publications

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

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

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

Transport of peptide and protein drugs across biological membranes

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The Oral Bioavailability of Peptides and Related Drugs

Cited by 26 publications

References 36 publications

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

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

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

Transport of peptide and protein drugs across biological membranes

Contact Info

Product

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

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