The oral route represents one of the most attractive andacceptable routes for the administration of thera-peutical compounds. The oral delivery of drugs and

proteins would avoid the pain and discomfort associatedwith injections, and would also eliminate the possibility ofinfections caused by the reuse of needles. Moreover, oralformulations are less expensive to produce, because theydo not need to be manufactured under sterile conditions.

Over the past few years, there has been an explosionin research aimed at creating new oral drug-deliverysystems. This research has been fuelled by unprec-edented challenges, such as the need to deliver the new,more-complex drugs (proteins, hormones, etc.) that arebecoming available through recombinant-DNA tech-nology. Considerable attention has thus been directedat finding ways to increase the intestinal permeabilityof these compounds. However, the intestinal absorp-tion of numerous compounds routinely used for thetreatment of common diseases is profoundly limited bytheir physicochemical characteristics.

Theoretically, three transepithelial pathways are avail-able for the passage of molecules from the intestinallumen to the bloodstream (Fig. 1): (1) transcellular (i.e.through the cell) carrier-mediated active or facilitatedtransport; (2) transcellular passive transport; and (3)paracellular (i.e. between adjacent cells) transport. Withthe exception of those molecules that are transportedby the first of these mechanisms, the absorption of largehydrophilic macromolecules is mainly limited to theparacellular pathway1. Under normal conditions, how-ever, this is restricted to molecules with molecular radii ,11 Å and is, therefore, not accessible to largecompounds. To overcome the intestinal barrier, severalstrategies have been developed to target either the trans-cellular or the paracellular pathway for drug delivery.The most promising techniques currently available will be reviewed, highlighting the advantages and disadvantages of each system.

Transcellular pathwayThe intestinal epithelium represents the largest

interface (.200 m2) between the external environmentand the internal host milieu, and constitutes a major barrier through which molecules can either be absorbed or secreted. Conceptually, the phospho-lipid bilayer of the plasma membrane of the epithelialcells that normally line the intestine (the enterocytes)is considered to be the major factor restricting the free movement of substances from the lumen to the bloodstream through the transcellular pathway. The uptake of hydrophobic molecules usually occursby passive transport, because the cell membrane behaves like an inert barrier and the molecules enter the cell by simple diffusion through the apical cell membrane. Facilitated and active transcellulartransport occur using specific carriers for smaller molecules, including sugars and amino acids, while the enterocyte membrane is almost impermeable tolarge hydrophilic substances such as proteins. There-fore, strategies have been developed that apply the prin-ciple of the ‘Trojan horse’: the macromolecules to bedelivered are hidden inside hydrophobic, biodegradablemicrospheres that can be taken up by endocytosis byintestinal cells (Fig. 1). Even if, theoretically, this seemsto be a solution to the problem, several factors mayaffect the extent of uptake of microparticles across thegut.

Size, surface and intestinal targetParticles currently used for drug delivery fall into two

classes: (1) nanoparticles, ranging in size from 10 to1000 nm and (2) microparticles, in the size range1–1000 mm. For oral delivery, nanoparticles seem to bemore efficiently absorbed, because the uptake of parti-cles within the intestine increases with decreasing par-ticle size and increasing hydrophobicity2. Furthermore,the extent and pathway of nanoparticle uptake is dif-ferent in different parts of the intestine3. The M cellsof the Peyer’s patches (Fig. 1) represent a sort of lym-phatic island within the intestinal mucosa and, possibly,the major gateway through which particles can beabsorbed.

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Innovative strategies for the oral delivery ofdrugs and peptidesAlessio Fasano

Conventional forms of administration for nonabsorbable drugs and peptides often rely on parenteral injection, because the

intestinal epithelium represents a major barrier to the oral absorption of these therapeutic agents. Recently, a number of

innovative drug-delivery approaches have been developed, including entrapment within small vesicles and passage through

the space between adjacent intestinal cells. This article reviews some of the most promising techniques currently available

for oral delivery and their possible practical applications for the delivery of vaccines and drugs for the treatment of clinical

conditions that require frequent, chronic parenteral administration.

A. Fasano (afasano@umaryland.edu) is at the Division of Pediatric Gastroenterology and Nutrition, and the GastrointestinalPathophysiology Section, Center for Vaccine Development, Universityof Maryland School of Medicine, Baltimore, MD 21201, USA.

152 Copyright © 1998, Elsevier Science Ltd. All rights reserved. 0167 – 7799/98/$19.00. PII: S0167-7799(97)01170-0 TIBTECH APRIL 1998 (VOL 16)

Dose and administration vehicleSeveral studies have shown that the intestinal uptake

of nanoparticles is dose dependent4,5. Le Fevre and Joel4have shown that nanoparticles could be identified inPeyer’s patches with difficulty after one day of feeding, but were readily identified following chronicfeeding. Peroral drug delivery may be further enhancedby the addition of mucoadhesive substances to thenanoparticles, with subsequent longer interaction ofthe particles with the cell membrane6. An alternativestrategy to increase the interaction of nanoparticles withtheir target cells is to mix them with lipid-deliveryvehicles such as lecithin7.

Species, age and food ingestionThe extent of nanoparticle uptake in rabbits seems

to be at least an order of magnitude greater than inmice, probably because of the much greater abundanceof M cells in the Peyer’s patches of rabbits8. The age ofthe animal also seems to affect particle uptake, with

greater absorption observed in older animals9. Thepresence of food seems to be another enhancing factorfor particle uptake, possibly because it may increase theintestinal transit time5.

Limitations of the transcellular pathway for drugdelivery

It should be pointed out that the term ‘uptake’ ofparticles for gut tissues may include both adsorbed par-ticles (i.e. particles that remain on the surface of theintestinal cells) and absorbed particles (i.e. particles thatare actually translocated to the bloodstream and aretherapeutically relevant). This means that the high figure reported in some of the literature for the parti-cle uptake10,11 is perhaps an over-estimatation of thelevels of actual absorption through the gut. Further-more, the macromolecules contained within the micro-spheres must, once taken up by the intestinal cell, escapedegradation by cellular lysosomes and then cross thebasolateral membrane in order to reach the bloodstream.

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Activetransport

Passivetransport

Particledelivery

M cell

To blood To blood

To lymph

Submucosa

Intestinal lumen

a b c

Figure 1Schematic representation of the three transepithelial intestinal pathways: (a) transcellular active transport; (b) transcellular passive trans-port; (c) paracellular transport. The carrier-mediated, transcellular active transport is limited to small molecules, such as sugars and aminoacids, but the other two pathways are theoretically available for the oral delivery of drugs and vaccines, because they do not require thepresence of specific carriers for the transepithelial transport of molecules. Transcellular passive transport may be enhanced by entrapmentof the active components in microspheres that are more efficiently taken up through the M cells; particles absorbed through intestinal epi-thelial cells (enterocytes) are subject to degradation by lysosomes and, therefore, less efficiently absorbed. The paracellular pathway maybe used for drug and peptide delivery by modulating the permeability of tight junctions.

For successful exploitation of particle uptake, it isnecessary that the process be both predictable andreproducible. Currently, there are contrasting data available describing the extent of particle uptake fol-lowing repeated administration to the same animal.Although some researchers have reported high levels of uptake10,12, others have only reported low uptakelevels4,5,13,14. The best method to quantify total particle uptake remains unknown and many of thestudies reviewed here were not designed with thisobjective in mind. For example, Jenkins et al.13 wereconcerned only with evaluating the relative extent ofuptake of alternative microparticle formulations of dif-ferent sizes. This study did not accurately determinethe total extent of particle uptake, because particlecounting was performed only from lymph and Peyer’s-patch samples.

The variable uptake of particles reported in the afore-mentioned studies makes it unlikely that the processcould be successfully applied to the delivery of a widerange of drugs. It may be possible, however, to use thistechnology for the oral delivery of drugs that have awide ‘therapeutic window’; that is, drugs that are activeat very low concentrations and show limited toxicity at much higher doses.

Transcellular pathway for vaccine deliveryA pathway responsible for the uptake of small num-

bers of particles is unlikely to be appropriate as a deliv-ery mechanism for a therapeutic dose of a drug, but itmight be adequate as a mechanism for stimulating a sig-nificant immune response to an orally deliveredmicroencapsulated antigen. The oral route for vaccinedelivery offers several advantages, including highpotential patient acceptance and compliance, less painand discomfort, and low costs of production andadministration, because trained personnel would not berequired to carry out immunizations. Consequently, anumber of vaccines would be significantly improved ifthey could be administered orally. Oral immunizationmight also result in improvements in vaccine efficacy,because oral immunization can stimulate mucosalimmunity. This might prove to be particularly advan-tageous in the elderly because, unlike systemic immun-ity, mucosal immunity does not appear to be subject toage-associated dysfunction. Oral immunization mightalso be attractive in the very young, because mucosalimmunity appears to develop earlier than systemic immunity.

The majority of the gut-associated lymphoid tissueis organized into aggregates of lymphoid follicles calledPeyer’s patches, whose major physiological role is theinduction of a secretory immune response to ingestedantigens. In humans, the largest Peyer’s patches arefound in the terminal ileum and are covered with a specialized epithelium that is adapted to allow antigensampling from the lumen. After contact, antigens aredelivered into the underlying dome structures of thepatches through specialized cells called M cells. Thereare two important aspects of the uptake and transportof antigens by M cells – (1) antigens will probablyescape degradation and (2) the antigen will be releasedinto an environment rich in immunocompetent cells(Fig. 1). Thus, uptake by M cells can enable the deliv-ery of intact antigens into the immunoinductive

environment of the Peyer’s patches. As mentionedabove, the M cell represents the favoured route fornanoparticle uptake, and so a great deal of research hasbeen focused on the delivery of antigens trapped in particles. Oral immunization with fimbriae from Bordetella pertussis entrapped in nanoparticles protectedmice from intranasal challenge with this pathogen15;whole viruses trapped in nanoparticles also inducedprotective immunity16,17. Oral immunization of micewith nanoparticles induced significant serum-IgG andsecretory-IgA antibody responses18; the secretory-IgAresponse was disseminated throughout the commonmucosal immune system18. Hence, oral immunizationwith microencapsulated vaccines potentially offers pro-tection against pathogens that infect the gut, the oralcavity and the respiratory and genital tracts.

Several alternative approaches to the oral delivery ofvaccines using polymeric delivery systems other thanmicroencapsulation have also been described, includ-ing the use of enteric coated polymers19, swellablehydrogels20 and the encapsulation of antigens in water-soluble polymers21. Each of these approaches may havepotential advantages over the use of microparticles, butthese have yet to be demonstrated.

Despite the promising results obtained in animalmodels, there are still major limitations to antigen deliv-ery through the transcellular pathway. These limitationsare mainly related to the small number of M cells present within the intestinal mucosa (,0.1% of epi-thelial cells). In the search for alternative solutions, sev-eral investigators have used the B subunit of choleratoxin (produced by Vibrio cholerae) as an adjuvant todeliver antigens orally via the enterocytes22. It has beendemonstrated that, under certain conditions, entero-cytes themselves can directly present antigens23. Theseobservations suggest that the delivery of oral vaccinesmight also be enhanced by harnessing the transcellularpathway of the major enterocyte population for anti-gen delivery, and perhaps even initial antigen process-ing. A fascinating alternative approach has beenrecently proposed by Kerneis et al.24, who described inan animal model how to stimulate the conversion ofenterocytes to an M-cell lineage, which transports anti-gens more efficiently across the intestinal barrier to theunderlying immune system.

Paracellular pathwayEpithelial cells of the intestine have apical intercellu-

lar attachments [the most important being the tightjunctions (tj)], which represent a barrier to the passageof macromolecules through the space between adjacentcells (the paracellular pathway, Fig. 1). A century ago,intestinal tj were thought to be a secreted extracellular‘cement’, forming an absolute and unregulated barrierwithin the paracellular space25. However, the assemblyof tj is the result of cellular interactions that trigger acomplex cascade of biochemical events, ultimatelyleading to the formation and modulation of an organ-ized network of tj elements, the composition of whichhas only been partially characterized26. There is now alarge body of evidence suggesting that tj play a pivotalrole in intestinal epithelial permeability. However, theutility of the paracellular route for oral drug deliveryhas remained unexplored owing to limited under-standing of tj physiology and the lack of substances

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capable of increasing tj permeability without irre-versibly compromising intestinal integrity and func-tion1,27,28. Indeed, attempts to increase paracellulartransport by loosening intestinal tj have been hamperedby unacceptable side effects induced by most of thepotential absorption-enhancing agents so fartested1,27,28. For the most part, these agents fall into twoclasses – calcium chelators and surfactants27. Both haveproperties that limit their general utility for promotingthe absorption of various molecules. In the case of calcium chelators, Ca21 depletion induces globalchanges in the cells, including disruption of actin fila-ments, disruption of adherent junctions and diminishedcell adhesion28. In the case of surfactants, the potentiallytic nature of these agents may cause exfoliation of theintestinal epithelium, irreversibly compromising its barrier functions27. Considering these limitations, it isreasonable to explore whether findings from basicresearch on tj regulation can be applied to developingnew approaches to enhancing drug absorption via the paracellular route.

To meet the many diverse physiological and patho-logical challenges to which epithelia are subjected, tjmust be capable of rapid and coordinated responses that require the presence of a complex regulatory system. The precise characterization of the mechanisms

involved in the assembly and regulation of tj is an activearea of current investigation. The discovery of Zonulaoccludens toxin (Zot), a protein produced by V. choleraethat increases the gut permeability29,30, has shed somelight on the intricate mechanisms involved in the regulation of intestinal tj. Zot increases the permeabil-ity of the small intestine by affecting the structure of tj29 via activation of a complex intracellular cascadeof events that regulate intestinal permeability31

(Fig. 2). Zot induces a dose- and time-dependent pro-tein kinase C (PKC) a-related polymerization of actinfilaments that are strategically located to regulate theparacellular pathway31.

Zot as a tool for oral drug delivery through the paracellular pathway

Zot displays multiple properties that might make it apromising tool to enhance drug and peptide transportthrough the intestinal mucosa: first, Zot is not cyto-toxic and does not affect the viability of the intestinalepithelium ex vivo29,31; second, it does not completelyabolish the intestinal transepithelial resistance29,31,32;third, it interacts with a specific intestinal receptorwhose regional distribution within the intestinevaries33; fourth, Zot is not effective in the large intes-tine, where the presence of the colonic microflora can

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Figure 2Zonula occludens toxin (Zot) intracellular signalling has been proposed to lead to the opening of intestinal tight junctions. Zot interacts witha specific surface receptor (1), whose distribution within the intestine varies. The protein is then internalized and activates phospholipase C(2), which then hydrolyses phosphatidyl inositol (3) to release inositol-1,4,5-triphosphate (PPI 3) and diacylglycerol (DAG) (4). Protein-kinaseCa (PKCa) is then activated (5), either directly (via DAG; 4) or through the release of intracellular Ca21 (via PPI 3; 4a). PKCa catalyses thephosphorylation of target protein(s), with subsequent polymerization of soluble G actin into F actin (7). This polymerization causes therearrangement of the filaments of actin and the subsequent displacement of proteins (including ZO-1) from the junctional complex (8). As aresult, intestinal tight junctions become looser, allowing the passage of macromolecules through the paracellular pathway.

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be harmful if the mucosal barrier is compromised32,33;fifth, it does not induce acute systemic side-effects (forat least 80–90 h) when orally administered32; sixth, and finally, it induces a reversible increase in tissue permeability29,31,32.

To establish the efficacy of Zot as an intestinal-absorption enhancer, insulin and immunoglobulin G(IgG) were selected as drugs to be delivered orally. Thischoice was based on the relative size, structure, biologi-cal activities and therapeutic relevance of these proteins.In vitro experiments in the rabbit ileum demonstratedthat Zot (1.1 3 10210 M) reversibly increases the intesti-nal absorption of both insulin (by 72%) and IgG (by52%) in a time-dependent manner32. The permeabi-lizing effect peaked at 80 min and was completelyreversible within 20 min after the withdrawal of themolecule. When tested in the intact host by using therabbit in vivo perfusion assay, Zot increased the passageof insulin across both the jejunum and distal ileum ten-fold, whereas no substantial changes were observed inthe colon32 (Fig. 3). Similar results were obtained withIgG, for which Zot induced twofold and sixfoldincreases in IgG absorption in the jejunum and ileum,respectively. Again, no increases in absorption weredetected in the colon32.

To evaluate the bioactivity of insulin after entericcoadministration with Zot, the hormone was orallyadministered to acute type-1-diabetic male rats with orwithout Zot, and the blood-glucose levels of the ratswere serially measured. After oral administration ofinsulin alone, given at doses between 5 and 30 Inter-national Units (IU), blood-glucose levels of treated ani-mals were not appreciably lowered32. By contrast, wheninsulin (at doses as low as 10 IU) was orally coadmin-istered with Zot [1.1 3 10210 moles (5 mg)], a signifi-cant reduction in blood-glucose concentration wasobserved (Fig. 4). This decrement was comparable tothat seen with a conventional dose of insulin admin-istered subcutaneously (range 1.2–2.4 IU); the blood-glucose levels returned to normal within 6 h afteradministration (Fig. 4). None of the animals treatedwith insulin and Zot experienced diarrhoea, fever orother systemic symptoms, and no structural changescould be demonstrated in the small intestine on histo-logical examination32.

Taken together, these results demonstrate that coad-ministration of Zot with biologically active ingredientsenhances intestinal absorption of the active molecule,and that this enhancement is effective for both relativelysmall (insulin, 5.7 kDa) and large (IgG, 140–160 kDa)molecules (Fig. 2). Furthermore, experiments in dia-betic rats demonstrate that orally delivered insulinretains its biological activity without provoking severehypoglycaemia within the range of the insulin admin-istered to the animals, that is, up to 15 times more thanthe effective parenteral insulin dose. These findingsmight have important practical implications, becausethe insulin therapeutic index (i.e. the ratio between themedian toxic dose and the median therapeutic dose) ofinsulin is relatively low.

ConclusionsOral delivery of drugs and vaccines represents the

‘Holy grail’ of pharmacological biotechnology. Con-sequently, numerous investigations are under way to

Time (min)

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Figure 3Effect of purified Zonula occludens toxin (Zot) on water (■; left axes)and insulin (■■; right axes) transport in rabbit jejunum, distal ileum and colon, as determined by the in vivo perfusion assay.Note the reversible increase in insulin absorption that Zot induced inthe small, but not in the large, intestine. This effect coincided withthe decreased absorption of water, a phenomenon related to the capillary hydrostatic pressure that is responsible for the secre-tion of water and electrolytes through the intestine made more permeable by Zot. Positive values refer to absorption, negative values to secretion. Reproduced from J. Clin. Invest. 99, 1158–1164(1997) by permission of the American Society for Clinical Investigation.

develop strategies to increase the intestinal absorptionof macromolecules. Although it is now generallyaccepted that uptake of particles across the intestineoccurs in animal models, a number of key unresolvedissues, such as intracellular trafficking and degradationof delivered macromolecules, still remain. Furthermore,the quantity, quality, predictability and reproducibilityof oral drug delivery through the transcellular pathwaymay limit the clinical use of this technology. Particleuptake may be easier to exploit clinically for the oraldelivery of vaccines, because the predominant site ofuptake, the Peyer’s patches, are the inductive sites formucosal immune response. Therefore, the use of theparacellular pathway may represent a better way toenhance the absorption of macromolecules not nor-mally absorbed through the intestine. Current knowl-edge of the regulation of intestinal tight junctions byZ. occludens toxin has been applied to explore the useof the paracellular pathway for drug delivery. The

results obtained in animal models represent an encour-aging basis for further studies to establish the possibleclinical applications of this system for the treatment ofhuman diseases that currently require frequent chronicparenteral drug administration.

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360300240180120600−225

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Figure 4Effect of oral insulin (10 IU), alone (■) or in the presence of Zot (5 mg)(■■) on serum glucose in diabetic rats. The coadministration of Zotwith insulin induced a reduction in blood-glucose concentration com-pared to that seen with a conventional dose of insulin administeredsubcutaneously (• ), and the blood-glucose levels returned normalby 6 h after administration. Blood-glucose levels of untreated ani-mals (•• ) and animals treated with oral Zot alone (▲) are shown forcomparison. These results would anticipate a relative oral insulinbioavailability of 20% when coadministered with Zot. Reproducedfrom J. Clin. Invest. 99, 1158–1164 (1997) by permission of theAmerican Society for Clinical Investigation.

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