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PubMed1990

Mechanism of clearance of dipeptides by perfused hindquarters: sarcolemmal hydrolysis of peptides.

The objective of the present experiment was to investigate the mechanism of clearance of a load of dipeptides (10 mumols) by perfused hindquarters of rats. The clearance was progressive over 60 min and was significantly (P less than 0.01) greater for glycylleucine than for glycylglycine (99 vs. 58% disappearance from the medium). Insulin had no significant effect on clearance of these dipeptides but stimulated the net uptake of their constituent amino acids. Investigation of the fate of peptides considered resistant to membrane hydrolysis showed a modest (24%) clearance for glycylsarcosine but a substantial one (89%) for glycylproline. Investigation of hydrolysis by sarcolemmal vesicles of skeletal muscle showed hydrolase activity against glycylglycine and glycylleucine but none against glycylsarcosine and glycylproline. Investigation of hydrolysis in the medium previously used to perfuse hindquarters for 60 min showed considerable activity against glycylleucine and glycylproline but none against glycylglycine and glycylsarcosine. These activities were entirely abolished by p-hydroxymercuribenzoate, an inhibitor of cytoplasmic peptide hydrolases. In conclusion, our data show that the mechanism of clearance of dipeptides by the perfused hindquarters is largely by hydrolysis, and the site of this hydrolysis differs for different dipeptides; hydrolysis is mediated either by plasma membrane enzymes, cytoplasmic enzymes released into the medium, or a combination of both.

Animals↗
PubMed1987

H+ gradient-driven dipeptide reabsorption in proximal tubule of rat kidney. Studies in vivo and in vitro.

Microinfusion of glycylsarcosine into superficial nephron sections showed that the dipeptide was reabsorbed mainly in late portions of the rat proximal tubule. In vivo microperfusion data demonstrated a saturable, high-capacity, low-affinity dipeptide reabsorption mechanism that was inhibited by other peptides but not by amino acids or peptidase inhibitors. The reabsorption was enhanced by lowering the luminal pH from 7.5 to 5.5. In vitro studies with rat cortical brush-border vesicles showed that glycylsarcosine uptake was independent of a Na+ gradient and greater uptake occurred when the extravesicular pH was acidic compared with the intravesicular pH. An inward-directed H+ gradient stimulated glycylsarcosine uptake and caused a transient accumulation of the dipeptide inside the vesicles above the equilibrium value. The presence of a proton ionophore abolished the H+ gradient-dependent uptake. An inside-negative membrane potential stimulated the initial uptake of the dipeptide. The uptake process was saturable and inhibited by other peptides but not by amino acids. The vesicle studies also showed that there are at least two peptide transport systems functioning in these vesicles, one a high-affinity, low-capacity type and the other a low-affinity, high-capacity type.

Amino Acids↗
PubMed2006

The dipeptide Arg-Gln inhibits retinal neovascularization in the mouse model of oxygen-induced retinopathy.

PURPOSE: Premature infants undergoing intensive care are highly vulnerable to amino acid deprivation. Supplementation of glutamine or arginine has resulted in beneficial effects in human neonates. This study was conducted to examine the effect of the dipeptide arginyl-glutamine (Arg-Gln) on vascular endothelial cell growth factor (VEGF) levels in primary human retinal pigment epithelial (hRPE) cell cultures and on inhibition of neovascularization in the oxygen-induced retinopathy (OIR) model. METHODS: The effects of Arg-Gln on VEGF levels were measured in supernates from hRPE cells by using ELISAs. For in vivo studies, mouse pups received twice-daily intraperitoneal injections of Arg-Gln, a control dipeptide (Ala-Gly) or were not injected. Retinal flatmounts from one cohort were prepared and retinal vessel morphology examined. The contralateral eyes were embedded, sectioned, and stained to count preretinal neovascular nuclei. RNA was isolated from retinas of selected animals and was used to quantify VEGF mRNA by real-time RT-PCR. RESULTS: Treatment of hRPE cells with Arg-Gln decreased VEGF levels in a dose-dependent manner. In the OIR model, Arg-Gln at 5 g/kg per day reduced preretinal neovascularization by 82%+/-7% (P<0.005), when compared with the control dipeptide Ala-Gly, and reduced VEGF mRNA by 64%+/-9% (P<0.001). CONCLUSIONS: Arg-Gln dramatically inhibited retinal neovascularization in the OIR model. This effect was associated with a reduction in retinal VEGF mRNA levels. Similarly the dipeptide reduced VEGF expression in hRPE cells, a cell type likely to respond to retinal hypoxia by expressing VEGF. Arg-Gln appears to be safe and, with future studies in human infants, may prove beneficial in the prevention of ROP.

Angiogenesis Inhibitors↗
PubMed1993

The potential use of parenteral dipeptides in clinical nutrition.

The metabolic effects of intravenous peptides have undergone extensive investigation in recent years. Dipeptide solutions provide a mechanism for the provision of selected amino acids that may be conditionally indispensable under certain clinical conditions. In particular, amino acids such as cystine, glutamine, and tyrosine may be difficult to provide in their free form, but their availability can be increased substantially when they are supplied in the form of a dipeptide. Animal and human studies have demonstrated that parenteral dipeptides are cleared rapidly from the plasma compartment and favorably influence nitrogen equilibrium in healthy volunteers and catabolic patients. Certain dipeptides offer the potential for tailoring tissue-specific nutrition therapy. It seems likely that parenteral peptides will offer a major change in the delivery of intravenous nutrients.

Animals↗
PubMed2000

Cyclic dipeptides in the induction of maturation for cancer therapy.

Studies have suggested a possible form of therapy based on the use of maturation-inducing compounds to induce differentiation of neoplastic cells and stimulate faster recovery of the normal cell population. The study of the effects of nine cyclic dipeptides on biochemical markers of differentiation implicated their potential to induce differentiation. Studies were undertaken to determine the specificity of these agents for HT-29 cell cultures as well as the identification of the signal transduction pathways affected by these agents inducing the differential gene expression observed in the cells. The cyclic dipeptides studied showed a high degree of specificity, having no significant effect on Caco-2 cells (P > 0.05), representing the normal gastrointestinal mucosa. All inducers administered were shown to affect the total energy state of HT-29 cells, an effect which increased the probability of HT-29 cell differentiation. Results indicated that those agents which induced differential gene expression acted at different steps in the isolated signal transduction pathway. Cyclo(Trp-Trp) and cyclo(Phe-Pro) induced a high degree of acetylation of histones (P < 0.05), while the remaining cyclic dipeptides induced a high degree of phosphorylation of histones (P < 0.05) (cyclo(Trp-Trp) induced a moderate degree of histone phosphorylation). The results from histone phosphorylation and acetylation and cyclic AMP responsive element binding protein phosphorylation studies suggest that the cyclic dipeptides activate a chromatin switch, which leads to the increase in accessibility of lineage-specific genes for transcription.

Antineoplastic Agents↗
PubMed2002

Uptake of cyclic dipeptide by PEPT1 in Caco-2 cells: phenolic hydroxyl group of substrate enhances affinity for PEPT1.

Uptake of cyclic dipeptides by H+/oligopeptide cotransporter (PEPT1) was studied in monolayers of the human intestinal cell line, Caco-2. The cyclic dipeptides studied were cyclic glycylphenylalanine (cyclo(Gly-Phe)), cyclic phenylalanylserine (cyclo(Phe-Ser)), cyclic seryltyrosine (cyclo(Ser-Tyr)) and cyclic glycyltyrosine (cyclo(Gly-Tyr)). These molecules have both peptide bonds and aromatic rings, and are similar in structure to cephalexin and cephadroxil, which are transported by PEPT1. Cellular uptake of these cyclic dipeptides was pH dependent, and was inhibited by the addition of PEPT1 substrates such as glycylsarcosine, indicating PEPT1-mediated transport. Michaelis constants (Km) for these cyclic dipeptides were cyclo(Ser-Tyr) < cyclo(Phe-Ser), and cyclo(Gly-Tyr) < cyclo(Gly-Phe), indicating that tyrosine possessing phenol moiety has higher affinity for PEPT1 than phenylalanine possessing benzen moiety. The Km for cephadroxil possessing phenol moiety was reportedly lower than that for cephalexin possessing benzen moiety. Therefore, it was concluded that the phenolic hydroxyl group of the substrate may enhance affinity for PEPT1.

Caco-2 Cells↗
PubMed1984

Intestinal absorption of several beta-lactam antibiotics. V. Effect of amino beta-lactam analogues and dipeptides on the absorption of amino beta-lactam antibiotics.

The absorption mechanism of amino beta-lactam antibiotics was investigated by using the whole small intestine of a rat. Mutual inhibition among amino beta-lactam analogues and the effects of dipeptides were studied. The influences of glycylglycine on the absorption of cephradine at the four different parts of intestine were also studied. Similarly to the case of cephalexin and cephradine, the absorption of amoxicillin was significantly inhibited by cyclacillin, cephradine, and cephalexin, but the absorption of ampicillin was not reduced by all tested antibiotics. In the experiments using dipeptides (6.0 mM), the absorption of cyclacillin was reduced significantly by glycylglycine, not by L-carnosine. And cephalexin absorption was influenced by L-carnosine (6.0, 10 mM), not by glycylglycine (6 mM). On the contrary, the absorption of cephradine was not reduced at all by these dipeptides. And from the experiment using the four different parts of intestine, it was shown that the transport interaction of glycylglycine with cephradine was observed in only one segment (the upper part of jejunum). These result suggest that the carrier-mediated transport system correlated to dipeptides participates only to a small degree in the common absorption mechanisms of these amino beta-lactam antibiotics.

Amoxicillin↗
PubMed1998

H(+)-coupled uphill transport of the dipeptide glycylsarcosine by bovine intestinal brush-border membrane vesicles.

In monogastric species, a considerable portion of amino acid nitrogen is absorbed across the brush-border membrane of the small intestine as small peptides (e.g., tripeptides and dipeptides). In ruminants, however, this process is less clear. Therefore, we investigated the uptake of radioactively labeled glycylsarcosine as a model dipeptide across the intestinal brush-border membrane using brush-border membrane vesicles prepared from the bovine small intestine. Uphill transport of glycylsarcosine was energized by a transmembrane H+ gradient and was further stimulated by an electrical potential difference across the membrane. Transport mediated by a carrier contributes to total glycylsarcosine transport across the brush-border membrane. Comparison of the apparent kinetic constants between brush-border membranes prepared from the proximal jejunum or ileum revealed similar half-saturating substrate concentrations (1.28 and 0.93 mmol/L for proximal jejunum and ileum, respectively), but maximal transport rates appeared to be somewhat higher in the proximal small intestine (2.15 and 1.20 nmol/mg of protein per 3 s for proximal jejunum and ileum, respectively). Uptake of glycylsarcosine was strongly inhibited by other dipeptides, but the amino acids glycine and sarcosine did not affect transport. Inhibition of glycylsarcosine uptake by cephalexin indicated an affinity of the carrier for cephalosporin antibiotics. Transport of intact dipeptides across the brush-border membrane of the small intestine might be of physiological importance in ruminants because the microbial and dietary proteins resistant to rumen degradation are digested and absorbed in the small intestine.

Animals↗
PubMed2006

Glutamine dipeptide for parenteral nutrition in abdominal surgery: a meta-analysis of randomized controlled trials.

AIM: To assess the clinical and economical validity of glutamine dipeptide supplemented to parenteral nutrition (PN) in patients undergoing abdominal surgery. METHODS: A meta-analysis of all the relevant randomized controlled trials (RCTs) was performed. The trials compared the standard PN and PN supplemented with glutamine dipeptide in abdominal surgery. RCTs were identified from the following electronic databases: the Cochrane Library, MEDLINE, EMBASE and ISI web of knowledge (SCI). The search was undertaken in April 2006. Literature references were checked by computer or hand at the same time. Clinical trials were extracted and evaluated by two reviewers independently. Statistical analysis was performed by RevMan4.2 software from Cochrane Collaboration. A P value of < 0.05 was considered statistically significant. RESULTS: Nine RCTs involving 373 patients were included. The combined results showed that glutamine dipeptide has a positive effect in improving postoperative cumulative nitrogen balance (weighted mean difference (WMD = 8.35, 95% CI [2.98, 13.71], P = 0.002), decreasing postoperative infectious morbidity (OR = 0.24, 95% CI [0.06, 0.93], P = 0.04), shortening the length of hospital stay (WMD= -3.55, 95% CI [-5.26, -1.84], P < 0.00001). No serious adverse effects were found. CONCLUSION: Postoperative PN supplemented with glutamine dipeptide is effective and safe to decrease the infectious rate, reduce the length of hospital stay and improve nitrogen balance in patients undergoing abdominal surgery. Further high quality trials in children and severe patients are required, and mortality and hospital cost should be considered in future RCTs with sufficient size and rigorous design.

Abdomen↗
PubMed2003

Changes of biological functions of dipeptide transporter (PepT1) and hormonal regulation in severe scald rats.

AIM: To determine the regulatory effects of recombinant human growth hormone (rhGH) on dipeptide transport (PepT1) in normal and severe scald rats. METHODS: Male Sprague-Dawley rats with 30% total body surface area (TBSA) III degree scald were employed as the model. In this study rhGH was used at the dose of 2 IU/kg(-1)d(-1). An everted sleeve of intestine 4 cm long obtained from mid-jejunum was securely incubated in Kreb's solution with radioactive dipeptide (3H-glycylsarcosine, 3H-Gly-Sar, 10 microCi/ml) at 37 degrees C for 15 min to measure the effects of uptake and transport of PepT1 of small intestinal epithelial cells in normal and severe scald rats. RESULTS: Abundant blood supply to intestine and mesentery was observed in normal and scald rats administered rhGH, while less supply of blood to intestine and mesentery was observed in rats without rhGH. Compared with controls, the transport of dipeptide in normal rats with injection of rhGH was not significantly increased (P=0.1926), while the uptake was significantly increased (P=0.0253). The effects of transport and uptake of PepT1 in scald rats with injection of rhGH were significantly increased (P=0.0082, 0.0391). CONCLUSION: Blood supply to intestine and mesentery of rats was increased following injection of rhGH. The effects of uptake and transport of dipeptide transporters in small intestinal epithelial cells of rats with severe scald were markedly up-regulated by rhGH.

Animals↗
PubMed2006

[A study on the discrimination of thermophilic and mesophilic proteins based on dipeptide composition].

In this work, the dipeptide composition of 3216 thermophilic and 4007 mesophilic protein sequences was systematically analyzed. We found that the thermophilic proteins contained more dipeptides such as EE, EK, KE, VE, EI, KI, EV, KK, VK and IE, whereas less dipeptides such as AA, LL, LA, AL, QA, QL, AQ, LT, TL and EQ. Based on this information, a statistical method for discriminating thermophilic and mesophilic proteins was developed. Our approach correctly picked up the thermophilic proteins with the accuracy of 94.0% and 89%, respectively, for the testing sets of 382 and 73 thermophilic proteins. And for the testing 325 and 73 mesophilic proteins, the accuracy was 85.2% and 89%, respectively. The influence of specific dipeptides on discrimination was also discussed.

Amino Acids↗
PubMedDate not supplied

Enzyme-inhibitory conformation of dipeptides containing sterically constrained amino acid 2,3-methanophenylalanine.

Dipeptides containing 2,3-methanophenylalanine, a sterically constrained amino acid with alpha,beta-cyclopropane ring, showed fairly strong inhibitory activity for the hydrolysis of Ac-L-Tyr-OEt by chymotrypsin. Kinetic analyses of the inhibition by dipeptides, H-inverted delta E Phe-Leu (or Phe)-OMe (or OH), indicated the mode of inhibition to be competitive. Comparative analyses of the inhibitory constants Ki have clarified several structural elements necessary to elicit an inhibitory activity. Those include the (2R,3S)-configuration of the inverted delta E Phe residue, the phenyl side chain at position 2 and the C-terminal methylesterification. These structural conditions suggested that the peptides are in specific inhibitory conformation. In the conformational analyses of these dipeptide inhibitors by a high resolution 1H-NMR (270 MHz), the measurement of enhancements of the nuclear Overhauser effect indicated that an intramolecular hydrophobic bonding exists between the inverted delta Phe-phenyl and ester-methyl to construct the hydrophobic core in the molecule. It was suggested that this hydrophobic core interacts with the chymotrypsin S2 site and prevents the hydrolysis of methyl ester. The Leu2 or Phe2 interacts with the enzyme S1 site. The structure of dipeptides containing 2,3-methanophenylalanine has been characterized as an enzyme-inhibitory conformation that interacts with the enzyme at its catalytic center.

Chymotrypsin↗
PubMed1990

[Effect of an angiogenesis-promoting dipeptide on microcirculation in experimental chronic stomach ulcer in the rat].

The influence of an angiogenesis stimulating dipeptide (Lys-Pro-derivative) on the blood flow rate of the stomach was tested in rats suffering from ulcus ventriculi by microspheres technique. 21 days after operation (acetic acid model by Takagi) the ulcers in the group treated with the dipeptide were healed completely, but not in the control group. The higher blood flow in the ulcer area of the dipeptide group radiometrically gained, was not changed significantly (U-test by Man-Whitney). These results demonstrate, that the process of rapid wound healing promoted by the dipeptide cannot entirely be explained by a higher blood flow of the stomach.

Angiogenesis Inducing Agents↗
PubMed1987

[Muscle dipeptides--natural inhibitors of lipid peroxidation].

The effects of carnosine (beta-alanyl-L-histidine) and anserine (beta-alanyl-1-methyl-L-histidine) on ascorbate-dependent lipid peroxidation in frog skeletal muscle sarcoplasmic reticulum were studied. It was found that the dipeptides (10-50 mM) cause a 25-90% inhibition of ascorbate-dependent lipid peroxidation and decrease the reaction rate and the amount of end products. The nature of lipid peroxidation primary products in the presence of the dipeptides changes which can be evidenced from changes in their spectral properties. Unlike other known natural antioxidants, skeletal muscle dipeptides do not only inhibit lipid peroxidation but also decrease the level of accumulated lipid peroxidation products. Histidine and beta-alanine, similar to imidazole, glycyl-glycine, arginyl-phenyl alanine and alpha-alanyl-D-histidine do not inhibit lipid peroxidation. At the same time, the carnosine stereoisomer D-carnosine which does not exist in nature exhibits a far greater inhibiting effect as compared to its natural counterpart. It is assumed that the skeletal muscle dipeptides carnosine and anserine are highly effective as natural antioxidants.

Animals↗
PubMed1986

Mechanisms of action of chloroalanyl antibacterial peptides. Identification of the intracellular enzymes inactivated on treatment of Escherichia coli JSR-O with the dipeptide beta Cl-LAla-beta Cl-LAla.

The dipeptide beta Cl-LAla-beta Cl-LAla is an antibacterial agent designed to utilize bacterial peptide transport for intracellular delivery of the alanine racemase inactivator beta Cl-LAla. The minimum inhibitory concentrations (MICs) for the peptide against Gram-negative species grown on enriched agar medium range from 1.56 to 12.5 micrograms/ml; MICs are increased to greater than 100 micrograms/ml when D-alanine is included in the medium, indicating that alanine racemase is, in fact, inhibited in sensitive species. When susceptible Gram-negative cells are grown on a minimal medium, D-alanine supplementation alone does not increase the MICs for beta Cl-LAla-beta Cl-LAla, but complete protection is afforded by supplementation with D-alanine, L-valine, L-leucine, and L-isoleucine. In liquid culture, the peptide is: bactericidal and lytic against Escherichia coli JSR-O growing in enriched medium or in minimal medium supplemented with the branched-chain amino acids; only inhibitory against these cells growing in minimal medium supplemented with D-alanine; and ineffective against these cells in minimal medium containing the branched-chain amino acids plus D-alanine. Cells exposed to beta Cl-LAla-beta Cl-LAla (with the protection of the four amino acids) have specific activities of both alanine racemase and transaminase B that are lower than those of cultures not treated with the peptide. Finally, E. coli JSR-O alanine racemase experiences time-dependent loss of activity when exposed to the dipeptide in the presence of aminopeptidases; the dipeptide alone is not an inactivator of the racemase in vitro. These results suggest the following mechanism of action for beta Cl-LAla-beta Cl-LAla: transport of the dipeptide into the cell; intracellular hydrolysis to give accumulation of beta Cl-LAla; and subsequent inactivation of targeted enzymes. Whether inactivation of the racemase or of the transaminase determines the pathophysiologic effects of the peptide depends on the composition of the growth medium.

Alanine Racemase↗
PubMed1983

Dipeptide formation with misacylated tRNAPhes.

Several misacylated P-site tRNAs have been prepared by the T4 RNA ligase-mediated coupling of Escherichia coli tRNAPhe missing the 3'-terminal cytidine and adenosine moieties and N-acetylaminoacyl-pCpA derivatives. The reaction proceeded in reasonable yield in each case and the tRNA products were purified conveniently by successive chromatographies on DEAE-cellulose and benzoylated DEAE-cellulose. The misacylated tRNAPhes were assayed for participation in the peptidyltransferase reaction, using E. coli ribosomes and poly(U) as message. When phenylalanyl-tRNAPhe was employed as the A-site tRNA, "chemically aminoacylated" N-acetyl-L-phenylalanyl-tRNAPhe produced dipeptide to virtually the same extent as authentic N-acetyl-L-phenylalanyl-tRNAPhe, which was prepared by enzymatic activation of tRNAPhe followed by chemical acetylation. Significant dipeptide formation was also obtained with N-acetyl-L-tyrosyl-tRNAPhe, but much less dipeptide was obtained when the D-isomers of these two N-acetylaminoacyl-tRNAs were employed in the same assay system. Interestingly, N-acetyl-beta-phenylalanyl-tRNAPhe formed dipeptide at least to the same extent as authentic N-acetyl-L-phenylalanyl-tRNAPhe.

Acylation↗
PubMed1995

Utilization of tyrosine-containing dipeptides and N-acetyl-tyrosine in hepatic failure.

The impact of hepatic dysfunction on the elimination and hydrolysis of three potential tyrosine sources for total parenteral nutrition, the dipeptides L-alanyl-L-tyrosine (Ala-Tyr) and glycyl-L-tyrosine (Gly-Tyr), and N-acetyl-L-tyrosine (Nac-Tyr) were evaluated in six patients with hepatic failure (five chronic, one acute) and seven healthy subjects. In controls, whole-body clearance (Cltot) of Ala-Tyr was higher than of Gly-Tyr (3,169 +/- 214 vs. 1,780 +/- 199 mL/kg/min, P < .01), and both exceeded clearance of Nac-Tyr (309 +/- 29 mL/kg/min, P > .01). Both dipeptides were hydrolyzed and released tyrosine immediately. In hepatic failure, elimination and hydrolysis of Ala-Tyr and Gly-Tyr were comparable to controls, but Cltot of Nac-Tyr was reduced (236 +/- 26 mL/kg/min). Neither in controls nor in patients an increase in plasma tyrosine concentration was seen after Nac-Tyr, and the major part of Nac-Tyr infused was lost in urine. The Cltot of tyrosine as evaluated after Ala-Tyr infusion (with the immediate release of tyrosine) was severely reduced in hepatic failure (152.7 +/- 38.4 vs. 484.4 +/- 41.4 mL/kg/min, P < .001) and half-life (kle) was retarded from 14.4 +/- 1.4 to 90.2 +/- 32.2 minutes (P < .03). The authors conclude that acute and chronic hepatic dysfunction does not affect elimination and hydrolysis of the dipeptides Ala-Tyr and Gly-Tyr and the constituent amino acids are released immediately. Nac-Tyr elimination was not grossly affected by hepatic failure, but neither in healthy subjects nor in hepatic failure patients was an increase of tyrosine seen. Both dipeptides but not Nac-Tyr may serve as a tyrosine source in parenteral nutrition. Moreover, by its rapid hydrolysis, the use of Ala-Tyr, for the first time, enables a simple rapid nonisotope evaluation of tyrosine kinetics for assessment of liver function.

Adult↗
PubMed1994

Transcellular transport of oral cephalosporins in human intestinal epithelial cells, Caco-2: interaction with dipeptide transport systems in apical and basolateral membranes.

The transport characteristics of p.o. cephalosporin antibiotics by monolayers of the human intestinal epithelial cell line Caco-2 were examined by measuring intracellular accumulation and transcellular transport. In the presence of an inward H+ gradient (at pH 6.0 of the apical medium), cephalosporins were accumulated by the monolayers in the following order: ceftibuten (anion) > cephradine (zwitterion) > cephalexin (zwitterion) > cefixime (anion). The accumulation rate of ceftibuten was more rapid than that of cephradine, whereas both appeared at the same rate in the basolateral compartment. The efflux of ceftibuten from the monolayers to the basolateral compartment was lower than the efflux of cephradine. The accumulation rate of ceftibuten from the basolateral side was markedly lower than that of cephradine. The accumulation of ceftibuten from both the apical and basolateral compartment was significantly inhibited by excess dipeptides. The kinetic parameters indicated that ceftibuten has higher affinity for the apical dipeptide transport system in the presence of a pH gradient, whereas it has much lower affinity for the basolateral dipeptide transport system at physiological pH of 7.4 than cephradine. These results suggest that both cephradine and ceftibuten are transported via the H+/dipeptide cotransport system localized in the apical membranes, and that the flux of these drugs across the basolateral membranes is also mediated by the dipeptide transport system in an H+ gradient-independent manner, exhibiting a rate-limiting step for their transcellular transport in Caco-2 monolayers.

Administration, Oral↗