Intestinal absorption of peptide drugs: advances in our understanding and clinical implications.

Abstract

Leading articleIntestinal absorption of peptide drugs: advances in our understanding and clinical implicationsThe route of administration of most drugs, including anti- biotics, is often decided empirically based on bioavailability data from animal studies.Increasing knowledge, however, of the transport mechanisms participating in solute uptake from the human intestine has improved our understanding of the absorption of peptide drugs (including a number of anti- biotics).This article will briefly discuss dipeptide transport in humans and then focus on the intestinal absorption ofpeptide drugs, in particular f-lactam antibiotics, and the therapeutic implications ofresearch in this field.f-lactam compounds are weakly acidic peptides and thus expected to be poorly absorbed from the gastrointestinal tract.Some ofthe drugs in this group, however, have surprisingly good oral bio- availability because of the utilisation of carrier mediated transport systems for small peptides within the brush border.Peptide compounds, particularly hormones and their analogues, are increasingly used therapeutically, although oral bioavailability is often a problem.Specific pharmacological design to facilitate intestinal absorption is potentially of great benefit.Design ofdrugs specifically to exploit carrier systems is important as the clinical usefulness of a compound is greatly enhanced if it is well absorbed when given by mouth.Mammalian peptide transport systems To reach the bloodstream from the gut lumen, solutes must either first cross the brush border membrane of the enterocyte microvilli, traverse the enterocyte cytoplasm, and exit by the basolateral membrane or enter by the paracellular route.Protein is predominantly absorbed from the mammalian gut as amino acids and oligopeptides, although some larger peptides may also be absorbed intact.'Absorption of these molecules entails both passive diffusion through the para- cellular pathways, and facilitated by carrier mediated trans- port.It is the use of these carrier mediated peptide transport systems in the absorption of peptide drugs that has recently provoked interest.Peptide transport in mammalian gut was first reported by Newey and Smyth more than 30 years ago.23 Peptide transport plays a major part in the absorption of amino acids and is therefore of nutritional significance.After luminal and brush border digestion by proteases, proteins are hydrolysed to a mixture of free amino acids, dipeptides, and a few tripeptides, which are suitable substrates for absorption into the enterocyte.4Much of the evidence for separate dipeptide and amino acid transport has been provided by studies in patients with Hartnup disease and cystinuria.In these conditions there is a genetic deletion, which results in an intestinal transport defect for neutral amino acids in Hartnup disease' and dibasic amino acids in cystinuria.'Despite these transport defects, however, the amino acids in question are absorbed normally or near normally when presented to the mucosa in the form of dipeptides.Furthermore, in most studies on dipeptide transport, uptake of the amino acid components of dipeptides is faster than that of the corres- ponding free amino acids, showing that different transport systems are involved."8Absorption of intact oligopeptides on