Effect of D-glucose on intestinal permeability and its passive absorption in human small intestine in vivo

BACKGROUND: Based on studies in animals, it has been proposed that carrier-mediated D-glucose absorption markedly enhances passive permeability of the jejunal mucosa, allowing the majority of D-glucose absorption to proceed passively. In this study, we evaluated this hypothesis in the human jejunum in vivo. METHODS: Using the constant perfusion, nonabsorbable marker technique, permeability of jejunal mucosa was assessed by measuring the ratio of diffusion rates of urea/L-xylose and mannitol/L-xylose. Passive D-glucose absorption was quantitated using L-glucose and mannitol as probes for D-glucose. RESULTS: Addition of D-glucose to perfused solutions did not change the diffusion ratios, indicating that D-glucose has no effect on the size of channels for passive diffusion across the jejunal mucosa. The fraction of total D-glucose absorption that could be attributed to a passive mechanism averaged 5%. In the human ileum in vivo, we detected no evidence of passive D-glucose absorption. CONCLUSIONS: Carrier-mediated D-glucose absorption does not increase passive permeability of human jejunal mucosa to solutes with molecular radii between 2.6 and 4.0 A. The amount of D-glucose absorbed passively from the human jejunum is trivial compared with the overwhelmingly dominant mechanism, carrier-mediated transport. Our results do not support the concept that sodium-dependent nutrient transport increases tight junction permeability.     

Genetic integrity of transforming growth factor beta (TGF-beta) receptors in cervical carcinoma cell lines: loss of growth sensitivity but conserved transcriptional response to TGF-beta

PURPOSE: Fractal kinetics was used for the analysis of the carrier-mediated transport for drugs across the intestinal epithelial cells. METHODS: The transport was examined under various agitation rates using a monolayer of Caco-2 cells and rabbit ileum sheets. RESULTS: The passive transport of antipyrine across Caco-2 cells was increased with the increasing rate of agitation and was supposed to be caused by a change in the thickness of the unstirred water layer. On the contrary, in the case of L-lactic acid transport, which follows a carrier-mediated transport mechanism, the more the agitation rate controlling the fractal dimension was increased, the more the permeability rate across the Caco-2 cells was decreased. Fractal kinetic analysis of L-lactic acid transport indicated that the permeability was caused by a single saturable process. Similar agitation effects with L-lactic acid transport were observed in the transport of phenylalanine and cephradine in Caco-2 cells. However, the permeability rates of benzoic acid and 3-O-methyl-D-glucose across Caco-2 cells and L-lactic acid transport across the rabbit ileum tissue indicated the maximum levels at a designated agitation rate. This phenomenon was likely to be caused by the agitation effects controlling not only the fractal environment but also the unstirred water layer. CONCLUSIONS: Carrier-mediated transports are well defined by fractal kinetics rather than classical kinetic analysis. Fractal kinetics are one of the important areas for understanding and confirming the properties of a carrier-mediated transport process.     

Postnatal catch-up growth induced by growth hormone and insulin-like growth factor-I in rats with intrauterine growth retardation caused by maternal protein malnutrition

In an earlier study, we found that yellow-rumped warblers had in vitro active uptake rates of D-glucose that were only a few percent of the glucose absorption rate achieved at the whole-animal level. Here we used a pharmacokinetic technique to test whether a substantial amount of sugar can be absorbed passively. We used yellow-rumped warblers (Dendroica coronata), known for their seasonal frugivory, freely feeding on a synthetic mash formulated with naturally occurring concentrations of D-glucose. Birds absorbed 89.8% +/- 1.0% (SE) of the D-glucose in the mash. When fed the same mash with trace-labeled 3H L-glucose, the stereoisomer that does not interact with the intestinal Na(+)-glucose cotransporter, 3H appeared in plasma, an indication that this stereoisomer of glucose was absorbed. We used 3H levels in plasma and excreta in a pharmacokinetic model to calculate L-glucose extraction efficiency (i.e., the percent absorbed). Calculated mean extraction efficiency for the passively absorbed L-glucose averaged 91% +/- 23%. Our finding of considerable passive absorption reconciles the in vitro and in vivo results for D-glucose absorption and is in concert with results from five other avian species. The passive pathway appears to provide birds with an absorptive process that can respond quickly to changing luminal concentration and that is energetically inexpensive to maintain and modulate in real time but that may bear a cost. Less discriminate passive absorption might increase vulnerability to toxins and thus constrain foraging behavior and limit the breadth of the dietary niche.     

Molecular cloning and functional expression in lactobacillus plantarum 80 of xylT, encoding the D-xylose-H+ symporter of Lactobacillus brevis

A 3-kb region, located downstream of the Lactobacillus brevis xylA gene (encoding D-xylose isomerase), was cloned in Escherichia coli TG1. The sequence revealed two open reading frames which could code for the D-xylulose kinase gene (xylB) and another gene (xylT) encoding a protein of 457 amino acids with significant similarity to the D-xylose-H+ symporters of E. coli, XylE (57%), and Bacillus megaterium, XylT (58%), to the D-xylose-Na+ symporter of Tetragenococcus halophila, XylE (57%), and to the L-arabinose-H+ symporter of E. coli, AraE (60%). The L. brevis xylABT genes showed an arrangement similar to that of the B. megaterium xylABT operon and the T. halophila xylABE operon. Southern hybridization performed with the Lactobacillus pentosus xylR gene (encoding the D-xylose repressor protein) as a probe revealed the existence of a xylR homologue in L. brevis which is not located with the xyABT locus. The existence of a functional XylR was further suggested by the presence of xylO sequences upstream of xylA and xylT and by the requirement of D-xylose for the induction of D-xylose isomerase, D-xylulose kinase, and D-xylose transport activities in L. brevis. When L. brevis was cultivated in a mixture of D-glucose and D-xylose, the D-xylose isomerase and D-xylulose kinase activities were reduced fourfold and the D-xylose transport activity was reduced by sixfold, suggesting catabolite repression by D-glucose of D-xylose assimilation. The xylT gene was functionally expressed in Lactobacillus plantarum 80, a strain which lacks proton motive force-linked D-xylose transport activity. The role of the XylT protein was confirmed by the accumulation of D-xylose in L. plantarum 80 cells, and this accumulation was dependent on the proton motive force generated by either malolactic fermentation or by the metabolism of D-glucose. The apparent affinity constant of XylT for D-xylose was approximately 215 microM, and the maximal initial velocity of transport was 35 nmol/min per mg (dry weight). Furthermore, of a number of sugars tested, only 6-deoxy-D-glucose inhibited the transport of D-xylose by XylT competitively, with a Ki of 220 microM.     

Concentration- and region-dependent intestinal permeability of fluvastatin in the rat

The purpose of this study was to investigate the mechanisms of transport of fluvastatin across the intestinal mucosa in various regions of the intestine in the rat. In-situ single-pass perfusions of the jejunum, ileum and colon were performed and the effective permeability (Peff) of fluvastatin, antipyrine and D-glucose were assessed in each region, at three different perfusate fluvastatin concentrations (1.6, 16 and 160 microM). The effect of lovastatin acid on the bi-directional transport of fluvastatin across the ileal mucosa was also studied. The Peff of fluvastatin was found to be dependent both on the intestinal region and on the concentration in the intestinal lumen (P < 0.001). Fluvastatin had the lowest Peff (0.55 +/- 0.10 x 10(-4) cm s(-1)) in the jejunum at 1.6 microM, and the highest Peff (1.0 +/- 0.16 x 10(-4) cm s(-1)) in the colon at 160 microM. The highest concentration of fluvastatin increased the average absorption of water from the intestine by 209% (P < 0.05), and the average Peff of D-glucose by 29% (P < 0.05). The presence of excess lovastatin acid (100 microM, compared with fluvastatin 1.6 microM) at the luminal side increased the average absorption of water by 218% (P < 0.001), and the Peff of fluvastatin in the ileum and the colon by 44 and 50%, respectively (P < 0.05). The presence of lovastatin acid on the luminal side in the ileum also increased the blood-to-lumen transport (exsorption) of fluvastatin by 43% (P < 0.001). The increased intestinal absorption of fluvastatin at higher concentrations does not suggest that substantial absorption occurs by any carrier-mediated process in the absorptive direction. The increased bi-directional transport when lovastatin acid was added to the lumen suggests that fluvastatin is not a P-glycoprotein substrate. Instead, the concentration-dependent increase in the absorption of fluvastatin, water and D-glucose suggests a direct effect of fluvastatin on the transcellular passive transport.     

Isoforms of myosin in growing muscles of ky (kyphoscoliotic) mice

The permeability of rat liver microsomes to glucose has been studied by using (14)C-labelled D-glucose and a light-scattering technique. 1) The microsomal intravesicular apparent isotope space for D-glucose (1mM; after 5 min incubation at 22 degrees C) was 2.34 microl/mg protein, i.e., approximately 72% of the apparent water space. 2) Efflux of [(14)C]D-glucose from microsomal vesicles pre-loaded as in 1) and measured by rapid Millipore filtration after dilution (100 fold) in a glucose-free medium revealed that 15 sec after dilution only 15% of intravesicular glucose was still retained by microsomes. 3) Osmotic behaviour of microsomes upon addition of D-glucose measured by a light-scattering technique revealed a glucose influx, saturable at [D-glucose] > 100 mM, and (partially) inhibited by pentamidine and cytochalasin B. Ascorbic acid, L-glucose and other monosaccharides and related compounds also permeated liver microsomes in a fashion similar to D-glucose. These data indicate the existence of a facilitative transport system(s) for glucose in the membrane of liver endoplasmic reticulum vesicles.     

Oral administration of rapamycin and cyclosporine differentially alter intestinal function in rabbits

The immunosuppressive drugs rapamycin (Rap) and cyclosporine A (CsA) are used clinically to modify or abolish immune-mediated functions. This study examined the effect of orally administered regimens of Rap, CsA, and a combination of Rap/CsA on intestinal function in male New Zealand white rabbits. Animals received oral doses of CsA (15 mg/kg/body weight/day), low-dose (LD) and high-dose (HD) Rap (0.25 or 1 mg/kg/body wt/day, respectively), or Rap/CsA (0.25 and 5 mg/kg/body wt/day, or 0.5 and 5 mg/kg/body wt/day, respectively) for 20 days. We measured in vitro uptake of nutrients and permeability, and morphometric measurements in the jejunum and ileum were made. Animals receiving HD-Rap or HD-Rap/CsA had decreased food intake, body weight, and intestinal weight, when compared with LD-Rap, LD-Rap/CsA, CsA, or controls. The maximal transport rate (Vmax) for the active jejunal uptake of D-glucose was increased in HD-Rap and CsA, but not in the HD-Rap/CsA-treated animals. The jejunal Vmax of D-glucose in the LD-Rap- or -Rap/CsA-treated animals was no different from controls. In the HD-Rap- and HD-Rap/ CsA-treated animals, jejunal rates of uptake of stearic, linoleic, and linolenic acids were reduced when compared with controls. Jejunal and ileal permeability (as assessed by the passive uptake of L-glucose, tissue conductance, and mucosal-to-serosal flux of [3H]inulin) was increased in animals treated with HD-Rap or HD-Rap/CsA, when compared with CsA or controls. These parameters of permeability were no different at lower doses of Rap or Rap/CsA. The jejunal and ileal villous surface area was increased in CsA, but decreased in HD-Rap or HD-Rap/CsA animals. Thus, HD-Rap given alone or in combination with CsA reduced body weight gain, in part due to reduced food intake and malabsorption of lipids, which was due at least in part to reduced intestinal surface area. The relevance of these findings to patients undergoing chronic immunosuppressive drug therapy needs to be established.     

Perfusion cells for studying regional variation in oral mucosal permeability in humans. 2. A specialized transport mechanism in D-glucose absorption exists in dorsum of tongue

To clarify the site of d-glucose absorption in human oral cavity, newly designed perfusion cells were applied to five different sites in the human oral cavity, i.e., the dorsum of the tongue, the ventral surface of the tongue, the labial mucosa, the floor of the mouth, and the buccal mucosa. The solution of D-glucose was perfused for 1 h and the rate of absorption was calculated from the amount that disappeared from the perfusate. D-Glucose was absorbed rapidly from the dorsum of the tongue and the absorption was saturable. The saturable absorption was also observed in the ventral surface of the tongue, but not in the other three sites. The rate of D-glucose absorption in the dorsum and the ventral surface of the tongue was significantly larger than that of L-glucose, while in the other sites they were not significantly different. The presence of a specialized transport system for D-glucose absorption in the dorsum of human tongue was suggested.     

Crystal structure of the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain

Phloridzin-insensitive D-glucose uptake into enterocytes isolated sequentially from along the crypt-villus axis showed the majority of transport activity to reside in cells from the upper third of the villus. In contrast, total postnuclear glucose transporter 2 (GLUT2) protein content of the cells was high even close to the crypt and was almost constant for the upper 80% of the villi. A 4 h lumenal perfusion in vivo with 100 mM D-glucose prior to harvesting the enterocytes produced a 2- to 3-fold increase in phloridzin-insensitive D-glucose uptake which extended down 70% of the villus. Vascular infusion in vivo with either 800 pM gastric inhibitory polypeptide (GIP) or glucagon-like peptide-2 (GLP-2) prior to harvesting enterocytes produced the same response as lumenal glucose, while glucagon like peptide-1 (GLP-1) had no effect. Inclusion of 30 microM brefeldin A (BFA), an inhibitor of protein trafficking, in the lumenal perfusate produced a small, but not significant, increase in the control uptake profile along the villus in isolated enterocytes. However, BFA significantly reduced the upregulation induced by lumenal glucose and vascular GIP and blocked the stimulation produced by vascular GLP-2. Biotinylation of surface proteins and isolation with protein A indicated that there was no change in the membrane abundance of GLUT2 after GLP-2 treatment. These results are discussed in relation to the role of gastrointestinal peptide hormones in controlling intestinal hexose transport and the possibility of protein trafficking being involved in mediating the upregulation of GLUT2 activity in the enterocyte basolateral membrane.     

Transport of glucose and leucine by intestinal membrane vesicles in genetic diabetes

Na+-dependent D-glucose and L-leucine uptakes by isolated small intestinal brush-border membrane vesicles were studied in normal and genetically diabetic mice (C57BL/KsJ-dbm). Vesicles from normal mice demonstrated transport characteristics and morphological appearances identical to those from other mammalian small intestinal brush-border membrane isolates. There was no difference found between genetically diabetic mice and their littermate controls. These data suggest that the small intestinal brush-border membrane transport is not altered in genetic diabetes in contrast to that found in drug-induced diabetes.     

Effect of total parenteral nutrition on amino acid and glucose transport by the human small intestine

OBJECTIVE: The effect of total parenteral nutrition (TPN) on small intestinal amino acid transport activity was studied in humans. SUMMARY BACKGROUND DATA: Studies in humans receiving TPN indicate that a decrease in the activities of the dissacharidase enzymes occurs, but morphologic changes are minimal with only a slight decrease in villous height. METHODS: Surgical patients were randomized to receive TPN (n = 6) or a regular oral diet (controls, n = 7) for 1 week before abdominal surgery. Ileum (5 controls, 5 TPN) or jejunum (2 controls, 1 TPN) were obtained intraoperatively and brush-border membrane vesicles (BBMV) were prepared by magnesium aggregation/differential centrifugation. Transport of L-MeAlB (a selective system A substrate), L-glutamine, L-alanine, L-arginine, L-leucine, and D-glucose was assayed by a rapid mixing/filtration technique in the presence and absence of sodium. RESULTS: Vesicles demonstrated approximately 18-fold enrichments of enzyme markers, classic overshoots, transport into an osmotically active space, and similar 1-hour equilibrium values. TPN resulted in a 26-44% decrease in the carrier-mediated transport velocity of all substrates except glutamine across ileal BBMVs. In the one patient receiving TPN from whom jejunum was obtained, there was also a generalized decrease in nutrient transport, although glutamine was least affected. Kinetic studies of the system A transporter demonstrated that the decrease in uptake was secondary to a reduction in carrier Vmax, consistent with a decrease in the number of functional carriers in the brush-border membrane. CONCLUSIONS: TPN results in a decrease in brush-border amino acid and glucose transport activity. The observation that glutamine transport is not downregulated by 1 week of bowel rest may further emphasize the important metabolic role that glutamine plays as a gut fuel and in the body's response to catabolic stresses.     

Modifier theory of meiotic drive: is Mendelian segregation stable?

1. Certain sugars were transported across the buccal mucosa by a carrier-mediated mechanism. 2. The metabolic loss of sugars from the mouth in a 5 min test period was negligible. 3. The buccal mucosal transport process was stereospecific for D-glucose and L-arabinose. 4. The absorption of D-glucose, galactose and 3-O-methyl-D-glucose was at least partly dependent on the presence of sodium ions in the luminal fluid. 5. The transport of D-glucose, was inhibited by galactose and 3-O-methyl-D-glucose, suggesting at least one common carrier system.     

Calcium channel blockers modify jejunal uptake of D-galactose in rabbits

Calcium channel blockers modify the intestinal uptake of lipids. This study was undertaken to test the hypothesis that two different types of calcium channel blockers influence the uptake of D-galactose, a sugar absorbed by the sodium-dependent glucose transporter (SGLT1) in the intestinal brush border membrane. Nisoldipine (1 mg/kg/day) or verapamil (4 mg/kg/day) were given by mouth to New Zealand white rabbits for three weeks, and then the rates of uptake of varying concentrations (2-64 mM) of galactose were examined in an in vitro preparation of jejunum using the incorporation of 14C-labeled substrate into intact tissue segments. The maximal transport capacities (Vmax) for D-galactose were increased in animals given nisoldipine or verapamil, as compared to controls. The value of the apparent Michaelis constant Km* for D-galactose was higher with nisoldipine group and lower with verapamil, than in controls. The apparent passive permeability (Pd*) of D-galactose was estimated from the uptake of L-glucose: Pd* was lower with nisoldipine and higher with verapamil, as compared to controls. The effect of these drugs on sugar uptake is not due to differences in the animals' food intake, body weight gain, or mucosal surface area. Thus, the two different classes of calcium channel blockers, the dihydropyridine nisoldipine and the phenylalkylamine verapamil, have different effects on the K(m)* and Pd*, but not on the Vmax of D-galactose uptake.     

Fluorescence study on ligand induced conformational changes of human erythrocyte glucose transporter

The nanosecond time-resolved fluorescence and fluorescence lifetime quenching have been used to detect the conformational changes of human erythrocyte glucose transporter induced by its ligands. Results show that D-glucose can decrease the fluorescence lifetimes, while L-glucose exhibits no effect. The fluorescence lifetime quenching results also show that in the presence of D-glucose, the quenching efficiency of hypocrellin B (a hydrophobic quencher obtained from a parasitic fungus, growing in Yunnan, China) is lower than in the presence of L-glucose. It can be deduced that the conformational changes of human erythrocyte glucose transporter induced by D-glucose are different from those induced by L-glucose.     

Assessment of thoracic aortic atheroma by echocardiography: a new classification and estimation of risk of dislodging atheroma during three surgical techniques

The purpose of this study was to determine whether the major thiol-disulfide oxidoreductase activities of the rat liver were altered as a consequence of aging, and whether the alterations had any consequences in terms of hepatic thiol concentrations. Liver fractions were prepared from male and female Fischer 344 rats at ages representing young adulthood (5 months), middle age (15 months) and old age (24-29 months), and the activities of the major thiol-disulfide exchange enzymes, together with protein and nonprotein sulfhydryl contents, were measured using spectrophotometric procedures. Thioltransferase, protein disulfide isomerase and thioredoxin reductase activities in livers of male and female rats were unchanged with aging, while glutathione disulfide (GSSG) reductase activity remained the same (in male livers) or increased (in female livers) as a consequence of aging. Both protein and nonprotein sulfhydryl concentrations were well maintained in old age. The absence of age-dependent alterations in the thiol-protein disulfide exchange enzymes and the lack of compromise in the glutathione GSSG reductase system suggest that aged livers retain their capacity to regulate their thiol-disulfide redox balance under normal physiological conditions.     

Intestinal absorption of peptides by coupling to bile acids

Poor intestinal absorption of peptides greatly limits their use as drugs for the treatment of chronic diseases. Since bile acids are efficiently absorbed by an active, Na(+)-dependent transport system in the ileum of mammals, model peptides of different chain length were attached to the 3-position of modified 3 beta-(omega-amino-alkoxy)-7 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acid. These peptide-bile acid conjugates inhibited Na(+)-dependent [3H]taurocholate uptake into brush-border membrane vesicles isolated from rabbit ileum in a concentration-dependent manner. Furthermore, photoaffinity labeling of the bile acid-binding proteins of M(r) 93,000 and 14,000, identified as the protein components of the ileal Na(+)-dependent bile acid transport system in rabbit ileum (Kramer, W., Girbig, F., Gutjahr, U., Kowalewski, S., Jouvenal, K., Müller, G., Tripier, D., and Wess, G. (1993) J. Biol. Chem. 268, 18035-18046) by the photoreactive taurocholate analogue, (3,3-azo-7 alpha, 12 alpha-dihydroxy-5 beta [7 beta, -12 beta-3H]cholan-24-oyl)-2-aminoethanesulfonic acid, was inhibited by the peptide-bile acid conjugates. In contrast, the parent peptides and amino acids neither had a significant effect on [3H]taurocholate uptake by ileal brush-border membrane vesicles nor on photoaffinity labeling of the ileal bile acid-binding membrane proteins. The inhibitory effect of peptide-bile acid conjugates on [3H]taurocholate transport and photoaffinity labeling of the bile acid-binding proteins in rabbit ileal vesicles decreased with increasing chain length of the attached peptide radical. By in vivo ileum perfusion in anesthetized rats an intestinal absorption of the bile acid conjugate S3744 of the fluorescent oxaprolylpeptide 4-nitrobenzo-2-oxa-1,3-diazol-beta-Ala-Phe-5-Opr-Gly (S1037) and secretion of the intact compound into bile could be demonstrated, whereas the parent peptide S1037 or its t-butylester S4404 were not absorbed. The intestinal absorption of S3744 showed a similar temperature dependence as [3H]taurocholate absorption and was inhibited by the presence of taurocholate indicating a carrier-mediated uptake of S3744 via the ileal bile acid transporter. In conclusion, these results indicate that oligopeptides can be made enterally absorable by coupling to modified bile acid molecules making use of the specific intestinal absorption pathway for bile acids. This finding may be of great importance for the design and development of orally active peptide drugs.     

Mathematical modelling of drug transport in emulsion systems

Two mathematical models for the prediction of drug transport in triphasic (oil, water and micellar) emulsion systems as a function of micellar concentration have been developed and these models were evaluated by comparing experimental and simulated data. Fick's first law was used to derive a transport model for hydrophilic drugs, assuming that the oil/water (o/w) partitioning process was fast compared with membrane transport and therefore drug transport was limited by the membrane. Consecutive rate equations were used to model transport of hydrophobic drugs in emulsion systems assuming that the o/w interface acts as a barrier to drug transport. Benzoic acid and phenol were selected as hydrophilic model drugs. Phenylazoaniline and benzocaine were selected as hydrophobic model drugs. Transport studies at pH 3.0 and 7.0 were conducted using side-by-side diffusion cells. According to the hydrophilic model, an increase in micellar concentration is expected to decrease drug transport rates. The effective permeability coefficients (Peff) of drugs were calculated using an equation relating Peff and the total apparent volume of drug distribution (determined experimentally using drug/membrane permeability and partition coefficient values). The hydrophobic model was fitted to the experimental data for the cumulative amount of model drug in the receiver cells using a weighted least-squares estimation program (PCNONLIN). The oil/continuous phase partitioning rates (k1) and the membrane transport rates (k2) were estimated. The goodness of fit was assessed from the correlation coefficients of plots of predicted versus experimental data. The predicted data were consistent with the experimental data for both the hydrophilic and hydrophobic models.     

Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2

It has been reported that conjugating acyclovir, a potent antiviral with low oral bioavailability, to L-valine increases its urinary excretion in rats. However, it was also reported that this increase is not found for the D-valine ester, suggesting that a carrier-mediated mechanism is involved in its intestinal absorption. Therefore, mechanisms involved in the transepithelial transport of L-valine-acyclovir were investigated using the intestinal cell line, Caco-2, as a model system for the intestinal epithelium. Only the mucosal-to-serosal transport of acyclovir was increased by conjugation with L-valine (approximately 7-fold), suggesting the involvement of a carrier-mediated mechanism. This conclusion was supported by the finding that this increase was saturable. The mucosal-to-serosal transport of L-valine-acyclovir could be inhibited by L-glycylsarcosine, but not by L-valine, suggesting the involvement of the dipeptide carrier. Also it was found that L-valine-acyclovir inhibits the uptake of cephalexin, a substrate for the oligopeptide transporter. Stability of the esters in either the mucosal or serosal bathing solution is more than 90% after completion of the transport study. However, after transport, the receiver solution contained approximately 90% of acyclovir. Based on these findings it was concluded that absorption of the L-valine ester of acyclovir occurs as a result of uptake by the oligopeptide transporter at the apical cell membrane followed by intracellular hydrolysis of the ester and efflux of acyclovir.     

Effect of serotonin treatment on intestinal transport in the rabbit

The hormone serotonin (5-hydroxytryptamine) has been implicated as the cause of the diarrhea seen in many patients with the carcinoid syndrome. To determine whether serotonin is an intestinal secretagogue, the effect of serotonin on intestinal water and electrolyte transport was evaluated in the rabbit. Two weeks of daily subcutaneous injection of serotonin suspended in oil resulted in a blood serotonin level elevated to twice that of controls. Intestinal transport was studied in vivo by a perfusion technique. Serotonin treatment resulted in ileal secretion and decreased mid-jejunal absorption of water and electrolytes but did not effect water absorption in the proximal jejunum or colon. Intestinal absorption of D-glucose and the amino acid L-tryptophan and glucose-dependent water and electrolyte absorption were normal in serotonin-treated animals. Serotonin-induced ileal secretion was reversed by methysergide, a peripheral antagonist of serotonin action. No alterations in intestinal histology or permeability occurred in serotonin-treated animals. Serotonin-induced intestinal secretion was not associated with alterations in the activities of intestinal mucosal adenylate cyclase, cyclic nucleotide phosphodiesterase, or Na-K-ATPase.     

Buccal absorption of enalapril and lisinopril

OBJECTIVE: The buccal absorption of captopril does not exhibit the classical pH/partition hypothesis, suggesting that mechanisms other than passive diffusion are involved in its absorption; animal studies have suggested that a peptide carrier-mediated transport system may be responsible for its absorption. The present study evaluated the effects of pH on octanol partitioning, and on the buccal absorption of enalapril and lisinopril, using in vitro techniques and buccal partitioning in human volunteer subjects. METHODS: The partitioning of enalapril and lisinopril into n-octanol was examined over the pH range of 3 9 at room temperature. RESULTS: Enalapril exhibited maximal partitioning into the organic phase at pH 4 5; minimal partitioning was recorded at pH values 8 and 9. The partitioning of lisinopril into n-octanol was found to be maximal at pH 9 and minimal at pH 3. Using the buccal absorption technique, the partitioning of enalapril and lisinopril (0.5 mg), was examined in six healthy male volunteers from buffered solutions (pH 3, 4, 5, 6, 7, 8 and 9). In the case of enalapril, lowest buccal partitioning occurred at pH 3, 8 and 9, while maximal partitioning occurred at pH 5; absorption of lisinopril was not extensive at any pH, but was greatest at pH 6. These results, in addition to the n-octanol partition coefficients, indicated that enalapril obeyed the normal lipid partition hypothesis with respect to buccal absorption. The buccal absorption of lisinopril also obeyed the lipid partition hypothesis over the pH range 3-7. These findings are in direct contrast to those for captopril. The buccal partitioning experiments were repeated at the maximal pH for absorption for each angiotensin converting enzyme (ACE) inhibitor, but with the addition of cephradine (0.05 mmol x l(-1)). CONCLUSION: The data indicated that the presence of this peptide transport inhibitor had no effect on the buccal absorption of enalapril (0.06 mmol x l(-1)) and lisinopril (0.057 mmol x l(-1)), which suggests that both drugs do not share a common buccal absorption pathway with cephradine.