Single-pass Intestinal Perfusion Model Research Articles

Differential absorption and metabolic characteristics of organic acid components in pudilan xiaoyan oral liquid between young rats and adult rats

Ethnopharmacological relevancePudilan Xiaoyan Oral Liquid (PDL) is a proprietary Chinese medicinal preparation approved by the State for treating acute pharyngitis in both adults and children (Approval No. Z20030095). It is worth noting that children exhibit unique physiopathological characteristics compared to adults. However, the in vivo regulatory characteristics of PDL in treating acute pharyngitis in children remain incompletely understood. Aim of the studyThe differential absorption and metabolism characteristics of the main pharmacological components in PDL in young and adult rats were investigated with a view to providing a reference for preclinical data of PDL in medication for children. Materials and methodsThis study utilized UPLC-Q-TOF-MS to investigate the pharmacodynamic material basis of PDL. The focus was on the gastrointestinal digestion and absorption characteristics of organic acid components in PDL (PDL-OAC), known as the primary pharmacodynamic components in this formulation. The research combined in vitro dynamic simulation and a Quadruple single-pass intestinal perfusion model to examine these characteristics. The permeability properties of PDL-OAC were evaluated using an artificial parallel membrane model. Additionally, an acute pharyngitis model was established to evaluate the histopathological condition of the pharynx in young rats using H&E staining. The levels of IL-1β, TNF-α, IL-6, and IL-10 in blood and pharyngeal tissue homogenates of young rats were quantified using ELISA kits. ResultsA total of 91 components were identified in PDL, including 33 organic acids, 24 flavonoids, 14 alkaloids, 5 terpenoids and coumarins, 3 sugars, and 12 amino acids. The PDL-OAC exhibited a significant reduction in IL-1β, TNF-α, IL-6, and IL-10 levels in the pharyngeal tissues of young rats with acute pharyngitis. Results from dynamic simulation studies of gastrointestinal fluids revealed that the PDL-OAC (Specifically chlorogenic acid (CGA), gallic acid (GA), chicoric acid (CRA), and caffeic acid (CA)) were effectively stabilized in the gastrointestinal fluids of both children and adults in vitro. Young rats, characterized by thinner intestinal walls and higher permeability, efficiently absorbed the four organic acids across the entire intestinal segment. The absorption of CGA, GA, and CRA followed a concentration-dependent pattern, with CGA and GA absorption being influenced by exocytosis. ConclusionThe efficacy of the PDL-OAC in treating acute pharyngitis was demonstrated in young rats. The absorption rate of these components was observed to be faster in young rats compared to adult rats, underscoring the need for dedicated studies on the drug's usage in children. This research provides valuable insights for the appropriate clinical use of PDL in pediatric patients.

Cluster-determinant 36 (CD36) mediates intestinal absorption of dietary astaxanthin and affects its secretion

The functional activity of dietary astaxanthin is closely related to its absorption, and the absorption of dietary carotenoids mainly mediated by transmembrane transport protein (TTP) has become the mainstream research direction in recent years. However, the main TTP mediating astaxanthin absorption and its potential mechanisms are still unclear. Hence, based on the preliminary screening results, this study aims to elucidate the role of cluster-determinant 36 (CD36) mediating astaxanthin absorption from the perspective of expression levels through in vitro cell model, in situ single-pass intestinal perfusion model and in vivo mice model. The results showed that astaxanthin uptake was significantly increased by 45.13% in CD36 overexpressing cells and decreased by 20.92% in the case of sulfo-N-succinimidyl oleate (SSO) inhibition. A similar trend also appeared in the duodenum and jejunum by in situ model. Moreover, astaxanthin uptake in the small intestine of CD36 knockout mice was significantly reduced by 88.22%. Furthermore, the inhibition or knockout of CD36 suppressed the expression of other transporters (SR-BI and NPC1L1). Interestingly, CD36 was also involved in the downstream secretion pathway, which is manifested by interfering with the expression of related proteins (ERK1/2, MTP, ApoB48, and ApoAI). Therefore, these results indicate the important role of CD36 in astaxanthin transmembrane transport for the first time, providing vital exploration way for the absorption of dietary fat-soluble substances.

Comparison of intestinal absorption characteristics between rhubarb traditional Chinese medicine preparation and activity ingredients using in situ and in vitro model

ObjectiveThe intestinal absorption characteristics of active ingredients are very important for oral administration of traditional Chinese medicine (TCM) to achieve the desired therapeutic effect. However, a deeper understanding about active ingredients absorption characteristics is still lack. The aim of this study was to investigate the absorption properties and mechanism of rhubarb active ingredients in TCM preparation and pure form. MethodsThe intestinal absorption behavior of active ingredients in Shenkang extract (SKE) and rhubarb anthraquinone ingredients (RAI) were investigated by in situ single-pass intestinal perfusion model. And the bidirectional transport characteristics of these active ingredients were assessed by in vitro Caco-2 cell monolayer model. ResultsIn situ experiment on Sprague-Dawley rats, the effective permeability coefficient values of aloe-emodin, emodin and chrysophanol in RAI were higher than those in SKE, and the value of rhein in RAI was lower than that in SKE. But the easily absorbed segments of intestine were consistent for all ingredients, whether in SKE or in RAI. In vitro experiment, the apparent permeability coefficient values of rhein, emodin and chrysophanol in RAI were higher than those in SKE, and this value of aloe-emodin in RAI was lower than that in SKE. But their efflux ratio (ER) values in SKE and RAI were all similar. ConclusionFour rhubarb anthraquinone ingredients in SKE and RAI have similar absorption mechanism and different absorption behavior, and the microenvironment of the study models influenced their absorption behavior. The results may provide an aid for understanding of the absorption characteristics of the TCM active ingredients in complex environments and the complementarities of different research models.

Pharmacokinetic assessment of cefpodoxime proxetil in diabetic rats.

In diabetes, multi-organ level dysfunction arising from metabolic complications is reported to influence the pharmacokinetics (PK) profile of many drugs. Hence, the present study was planned in rats to evaluate the effect of diabetes on the PK profile of cefpodoxime, a widely prescribed oral antibiotic. PK profile of cefpodoxime was assessed after oral administration of cefpodoxime proxetil (10 and 20mg/kg) and intravenous (i.v) administration of cefpodoxime sodium (10mg/kg) in normal and streptozotocin induced diabetic rats. To evaluate the impact of diabetes on oral absorption and serum protein binding, in situ intestinal permeability and in vitro serum protein binding studies were performed for cefpodoxime using Single Pass Intestinal Perfusion model (SPIP) and ultracentrifugation technique, respectively. In diabetic rats, there was significant (p < 0.01) decrease in maximum concentration (Cmax) and area under the curve (AUC) of cefpodoxime by both oral and intravenous route, which was attributed to augmented clearance of cefpodoxime. There was no change in the time to achieve Cmax (Tmax) suggesting no alteration in oral absorption which was further confirmed through unaltered intestinal permeability in diabetic rats. The protein binding in diabetic rats also remained unchanged, indicating no influence of protein binding on elevated clearance. The plasma exposure of cefpodoxime, a renally eliminated drug was significantly lowered in diabetic rats due to enhanced glomerular filtration. However, this observation needs to be confirmed through well controlled clinical trials.

Development of Paeonol Liposomes: Design, Optimization, in vitro and in vivo Evaluation.

BackgroundUlcerative colitis (UC) is one of the intractable diseases recognized by the World Health Organization, and paeonol has been proven to have therapeutic effects. However, the low solubility of paeonol limits its clinical application. To prepare and optimize paeonol liposome, study its absorption mechanism and the anti-inflammatory activity in vitro and in vivo, in order to provide experimental basis for the further development of paeonol into an anti-inflammatory drug in the future.MethodsPaeonol loaded liposomes were prepared and optimized by thin film dispersion-ultrasonic method. The absorption mechanism of paeonol-loaded liposomes was studied by pharmacokinetics, in situ single-pass intestinal perfusion and Caco-2 cell monolayer model, the anti-inflammatory activity was studied in a mouse ulcerative model.ResultsBox-Behnken response surface methodology permits to screen the best formulations. The structural and morphological characterization showed that paeonol was entrapped inside the bilayer in liposomes. Pharmacokinetic studies found that the AUC0-t of Pae-Lips was 2.78 times than that of paeonol suspension, indicating that Pae-Lips significantly improved the absorption of paeonol. In situ single intestinal perfusion and Caco-2 monolayer cell model results showed that paeonol was passively transported and absorbed, and was the substrate of P-gp, MRP2 and BCRP, and the Papp value of Pae-Lips was significantly higher than that of paeonol. In vitro and in vivo anti-inflammatory experiments showed that compared with paeonol, Pae-Lips exhibited excellent anti-inflammatory activity.ConclusionIn this study, Pae-Lips were successfully prepared to improve the oral absorption of paeonol. Absorption may involve passive diffusion and efflux transporters. Moreover, Pae-Lips have excellent anti-inflammatory activity in vitro and in vivo, which preliminarily clarifies the feasibility of further development of Pae-Lips into oral anti-inflammatory drugs.

Effect of berbamine hydrochloride on the absorption of berberine hydrochloride in an in situ single-pass intestinal perfusion system in rats

Purpose: To investigate the intestinal absorption characteristics of berberine hydrochloride (BBH) under different perfusion conditions in rats.Methods: Based on the in situ single-pass intestinal perfusion model of rats, HPLC was used to determine the content of berberine hydrochloride in solution after perfusion under different conditions. The absorption rate constant (Ka), effective permeability coefficient (Papp) and cumulative absorption per unit area (Q) under different perfusion conditions were analyzed by one-way ANOVA.Results: The Papp and Ka of BBH in perfusion solution at pH 7.4 were greater than those in perfusion solution at pH 6 and 8. There was no significant difference (p &gt; 0.05) in Papp and Ka of duodenum, jejunum and ileum at high, medium and low concentrations of berberine hydrochloride perfusion solution. The Q increased linearly with increase of mass concentration of perfusion solution. The Ka and Papp of BBH in duodenum, jejunum, and ileum of BBH and berbamine hydrochloride (BAH) combined at different ratios were higher than those of BBH control group at the same BBH concentration, but absorption of BBH in the ratio B40:A50 and B30:A20 groups was highest. In the ratio of B40:A50 ratio, B30:A20 ratio group or the same concentration's BBH group, Ka and Papp of BBH decreased in the order of jejunum &gt; duodenum &gt; ileum.Conclusion: Berberine hydrochloride is absorbed in neutral environment of pH 7.4. The intestinal absorption mechanism of BBH is passive diffusion, and jejunum is the best intestinal segment for absorption. BAH promotes the absorption of BBH.

Intestinal absorption mechanism of rotundic acid: Involvement of P-gp and OATP2B1

Ethnopharmacological relevanceIlicis Rotundae Cortex (IRC), the dried barks of Ilex rotunda Thunb. (Aquifoliaceae), has been used for the prevention or treatment of colds, tonsillitis, dysentery, and gastrointestinal diseases in folk medicine due to its antibacterial and anti-inflammatory effects. However, there is no report about the intestinal absorption of major compounds that support traditional usage. Aim of studyConsidering the potential of rotundic acid (RA) – major biologically active pentacyclic triterpenes found in the IRC, this study was purposed to uncover the oral absorption mechanism of RA using in situ single-pass intestinal perfusion (SPIP) model, in vitro cell models (Caco-2, MDCKII-WT, MDCKII-MDR1, MDCKII-BCRP, and HEK293-OATP2B1 cells) and in vivo pharmacokinetics studies in rats. Materials and methodsThe molecular properties (solubility, lipophilicity, and chemical stability) and the effects of principal parameters (time, compound concentrations, pH, paracellular pathway, and the different intestinal segments) were analyzed by liquid chromatography-tandem mass spectrometry. The susceptibility of RA to various inhibitors, such as P-gp inhibitor verapamil, BCRP inhibitor Ko143, OATP 2B1 inhibitor rifampicin, and absorption enhancer EGTA were assessed. ResultsRA was a compound with low water solubility (12.89 μg/mL) and strong lipophilicity (LogP = 4.1). RA was considered stable in all media during the SPIP and transport studies. The SPIP and cell experiments showed RA was moderate absorbed in the intestines and exhibited time, concentration, pH, and segment-dependent permeability. In addition, results from the cell model, in situ SPIP model as well as the in vivo pharmacokinetics studies consistently showed that verapamil, rifampicin, and EGTA might have significant effect on the intestinal absorption of RA. ConclusionThe mechanisms of intestinal absorption of RA might involve multiple transport pathways, including passive diffusion, the participation of efflux (i.e., P-gp) and influx (i.e., OATP2B1) transporters, and paracellular pathways.

Effect of Vitamin C on Absorption Characteristics of Nimodipine and Nitrendipine in an in Situ Rat Single-Pass Intestinal Perfusion Model

Effect of Vitamin C on Absorption Characteristics of Nimodipine and Nitrendipine in an in Situ Rat Single-Pass Intestinal Perfusion Model

Studies on the Incompatibility between Bulbus fritillariae and Radix aconiti praeparata Based on the P-gp.

Bulbus fritillariae and Radix aconiti praeparata are an incompatible herbal pair in the traditional Chinese medicine theory “eighteen incompatible medicaments,” and they should not be used simultaneously in clinical treatment for safety. This study aimed to investigate the incompatibility mechanism between Bulbus fritillariae and Radix aconiti praeparata based on their interaction with P-glycoprotein (P-gp). The interaction between Bulbus fritillariae and Radix aconiti praeparata during in vitro decocting as well as in vivo absorption was investigated by determining the dry extract yield and by rat single-pass intestinal perfusion (SPIP) model. Inhibition of different species of Bulbus fritillariae on P-gp function was examined using the SPIP model. The mRNA and protein expression of P-gp was determined by PCR and western blotting. The active ingredients of Bulbus fritillariae were predicted and screened for inhibiting P-gp activity by Schrodinger's molecular docking and MDR1-MDCK cell transport study, respectively. Mediation of monoester alkaloids in Radix aconiti praeparata by P-gp was predicted and examined using Schrodinger's molecular docking and SPIP experiment, respectively. In the results, when Radix aconiti praeparata was combined with Bulbus fritillariae, the toxic ingredient benzoylmesaconine in Radix aconiti praeparata displayed higher intestinal permeability, whereas the toxic ingredients showed no significant difference during the in vitro decoction process. Bulbus fritillariae thunbergii inhibited both the P-gp function and expression; in contrast, Bulbus fritillariae cirrhosae inhibited the function only. Alkaloids including peimine, peimisine, and imperialine were the active ingredients for inhibiting P-gp activity. Benzoylmesaconine in Radix aconiti praeparata was the substrate of P-gp.

Effect of Coformer Selection on In Vitro and In Vivo Performance of Adefovir Dipivoxil Cocrystals.

This study aimed to improve the in vitro dissolution, permeability and oral bioavailability of adefovir dipivoxil (ADD) by cocrystal technology and clarify the important role of coformer selection on the cocrystal's properties. ADD was cocrystallized with three small molecules (i.e., paracetamol (PA), saccharin (SAC) and nicotinamide (NIC)), respectively. The obtained ADD-PA cocrystal was characterized by DSC, TGA, PXRD and FTIR. Comparative study on dissolution rates among the three ADD cocrystals were conducted in water and pH 6.8 phosphate buffer. Besides, effects of coformers on intestinal permeability of ADD were evaluated via in vitro Caco-2 cell model and in situ single-pass intestinal perfusion model in rats. Furthermore, in vivo pharmacokinetic study of ADD cocrystals was also compared. Dissolution rates of ADD cocrystals were improved with the order of ADD-SAC cocrystal > ADD-PA cocrystal > ADD-NIC cocrystal. The permeability studies on Caco-2 cell model and single-pass intestinal perfusion model indicated that PA could enhance intestinal absorption of ADD by P-gp inhibition, while SAC and NIC did not. Further in vivo pharmacokinetic study showed that ADD-SAC cocrystal exhibited higher Cmax (1.4-fold) and AUC0-t (1.3-fold) of ADD than administration of ADD alone, and Cmax and AUC0-t of ADD-PA cocrystal were significantly enhanced by 2.1-fold and 2.2-fold, respectively, which was attributed to its higher dissolution and improved intestinal permeability. Coformer selection had an important role on cocrystal's properties, and cocrystallization of ADD with a suitable coformer was an effective approach to enhance both dissolution and bioavailability of ADD.

The influence of rhein on the absorption of rehmaionoside D: In vivo, in situ, in vitro, and in silico studies

Ethnopharmacological relevanceIn traditional Chinese Medicine, Rehmannia glutinosa (Gaertn.) DC., as the principle herb of ShengDiHuang Decotion (SDHD), has the effect of cooling blood and hemostasis, and tonifying the yin and kidney. Rheum L., as adjuvant herbs, assist Rehmannia glutinosa (Gaertn.) DC. to promote blood circulation to remove blood stasis. Aim of studyTo study the mechanism of Rhein (RH) involved in the promotion of Rehmannioside D (RD) absorption by pharmacokinetic studies, single-pass intestinal perfusion, Caco-2 cell models, molecular docking technique and western blotting. Materials and methodsInitially, the intestinal absorption of RD in the presence or absence of RH was conducted through pharmacokinetic studies. Thereafter, the intestinal absorption of RD and RH was studied using the single-pass intestinal perfusion and Caco-2 cell models. Finally, using molecular docking technique and western blotting. ResultsWe found that the promotion of RD absorption by RH was mediated by breast cancer resistance and multidrug resistance-associated protein 2, thereby affecting the permeability of the intestinal epithelium. Additionally, RH and RD can competitively bind to breast cancer resistance and multidrug resistance-associated protein 2, and that RH inhibits the expression of breast cancer resistance and multidrug resistance-associated protein 2 in the ileum to promote the intestinal absorption of RD. ConclusionThis study reveals the mechanisms associated with the RH-mediated promotion of RD absorption and provides a basis for further exploring the synergistic effect of Rehmannia glutinosa (Gaertn.) DC and rhubarb.

PH-sensitive dual drug loaded janus nanoparticles by oral delivery for multimodal analgesia

BackgroundBased on the concept of “multimodal analgesia”, a novel dual drug delivery system was designed to achieve synergistic analgesia between najanajaatra venom protein (αCT) and resveratrol (Res). In order to meet the joint loading of two drugs with different physicochemical properties without affecting each other, an oral Janus nanoparticle (JNP) with a unique cavity structure and synergistic drug delivery was constructed using an improved double emulsion solvent evaporation method, and combined with low-molecular-weight chitosan/sodium alginate and PLGA to achieve its pH-responsive.ResultsThe synthesized αCT/Res-JNPs are homogeneous in shape, with a two-compartment structure, approximately 230 nm in size, and zeta potential of 23.6 mV. Drug release assayed in vitro show that JNP was stable in simulated gastric juice (pH = 1.2) but was released in phosphate buffer saline (pH = 7.4). After intragastric administration in rats, PK evaluation showed that αCT/Res-JNPs could significantly improve the oral bioavailability, and the simultaneous encapsulation of the two drugs had no significant interaction on PK parameters. An obvious synergistic analgesic effects of αCT/Res-JNPs was confirmed in a spinal cord injury and acute pain model. Confocal laser scanning microscopy and single-pass intestinal perfusion model provided strong evidence that αCT/Res-JNPs could pass through intestinal epithelial cells, and the endocytosis pathway was mainly involved in the mediation and pinocytosis of reticulin. The concentrations of αCT and Res from αCT/Res-JNP in lymphatic transport were only about 8.72% and 6.08% of their blood concentrations at 1 h, respectively, which indicated that lymphatic transport in the form of JNP has limited advantages in improving the oral bioavailability of Res and αCT. Cellular uptake efficiency at 4 h was about 10–15% in Caco-2 cell lines for αCT/Res-JNP, but was reduced to 7% in Caco-2/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 12–17% of αCT/Res-JNP were transported across Caco-2/HT29-MTX/Raji monolayers. The cumulative absorption of JNP in three cell models was higher than that of free drug.ConclusionsThis study investigated the contribution of Janus nanoparticles in oral absorption, and provide a new perspective for oral administration and analgesic treatment of dual drug delivery system containing peptide drugs.Graphic

Effect and molecular mechanism research of Astragalus membranaceus on inhibiting intestinal absorption of six alkaloids of Aconitum carmichaelii in spleen deficiency rats

ObjectiveTo investigate the effect and the mechanism of Astragalus membranaceus (Huangqi in Chinese, HQ) extract on the intestinal absorption of six alkaloids of Aconitum carmichaelii (Fuzi in Chinese, FZ) in rats with spleen deficiency and provide novel insights into the application of HQ on modulating intestinal barrier. MethodsFour-week-old male Sprague-Dawley rats were fed with Xiaochengqi Decoction to induce the spleen deficiency model for 40 d. Single-pass intestinal perfusion model were used to study the effects of HQ extract on the absorption of alkaloids. Protein expression and mRNA levels of MRP2 and BCRP and tight junction proteins (TJ, including Claudin-1, Occludin and ZO-1) were measured using Western blot and real-time PCR, respectively. The location and expression of TJ protein was also investigated by the immunofluorescence method. ResultsCompared with the normal group, the protein expression of MRP2, BCRP and TJ proteins in the model group were significantly down-regulated. After oral administration of HQ, the alkaloid absorption in intestinal villi was inhibited, MRP2, BCRP and TJ proteins were up-regulated, the green fluorescence staining of Claudin-1, Occludin, and ZO-1 was enhanced, and a thick layer of mucus was deposited on the surface of the epithelium of the intestinal cavity. ConclusionHQ as an intestinal barrier modulator improves the physiological changes of the intestinal environment of spleen deficiency to reduce the absorption of toxic components, leading to a decrease in the absorption of drug-like molecules.

Liquiritin enhancing intestinal absorption of paeoniflorin in in situ single-pass intestinal perfusion and in vitro Caco-2 cell monolayer absorption models

Background: Paeoniflorin and liquiritin are the primary active components of Shaoyao-Gancao-tang (SGT), a classical prescription for reducing pains. However, the interaction of paeoniflorin and liquiritin during intestinal absorption needs to be further studied. Objectives: In this study, we aimed to determine the interaction of paeoniflorin and liquiritin during intestinal absorption. Materials and Methods: The interaction between paeoniflorin and liquiritin (100 μM) was studied using in situ single-pass intestinal perfusion (SPIP) model use the whole small intestine and in vitro Caco-2 cell monolayer bidirectional transport model. Results: In situ SPIP research demonstrated that liquiritin significantly increased the Ka, Papp, absorption rate, and cumulative amount of paeoniflorin up to 7.97, 8.98, 7.07, and 10.71 folds, respectively, even higher than that of verapamil, a specific P-gp inhibitor, and control. Furthermore, 18 β-glycyrrhetinic acid (18 β-GA) markedly increased the Ka, Papp, absorption rate, and cumulative amount of paeoniflorin up to 3.30, 3.27, 3.42, and 4.04 folds, respectively. Bidirectional transport studies indicated that liquiritin and paeoniflorin could prompt the absorption of each other by increasing the Papp (AP-BL) of paeoniflorin and liquiritin from (3.83 ± 0.51) ×10−7 to (5.60 ± 0.51) ×10−7 cm/s and (3.86 ± 0.34) ×10−7 to (8.26 ± 0.51) ×10−7 cm/s, respectively. The 18 β-GA significantly prompted the Papp (AP-BL) of paeoniflorin to (5.54 ± 0.92) ×10−7 cm/s. Conclusion: Liquiritin and paeoniflorin increased the absorption of each other. This could provide essential reference to predict the oral bioavailability, the pharmacokinetics, and the clinical application of coadministration of liquiritin-and paeoniflorin-containing SGT and other herbal formulas.

Oleacein Intestinal Permeation and Metabolism in Rats Using an In Situ Perfusion Technique.

Oleacein (OLEA) is one of the most important phenolic compounds in extra virgin olive oil in terms of concentration and health-promoting properties, yet there are insufficient data on its absorption and metabolism. Several non-human models have been developed to assess the intestinal permeability of drugs, among them, single-pass intestinal perfusion (SPIP), which is commonly used to investigate the trans-membrane transport of drugs in situ. In this study, the SPIP model and simultaneous luminal blood sampling were used to study the absorption and metabolism of OLEA in rats. Samples of intestinal fluid and mesenteric blood were taken at different times and the ileum segment was excised at the end of the experiment for analysis by LC–ESI–LTQ–Orbitrap–MS. OLEA was mostly metabolized by phase I reactions, undergoing hydrolysis and oxidation, and metabolite levels were much higher in the plasma than in the lumen. The large number of metabolites identified and their relatively high abundance indicates an important intestinal first-pass effect during absorption. According to the results, OLEA is well absorbed in the intestine, with an intestinal permeability similar to that of the highly permeable model compound naproxen. No significant differences were found in the percentage of absorbed OLEA and naproxen (48.98 ± 12.27% and 43.96 ± 7.58%, respectively).

Promoting effect of the Maillard reaction products produced during the stir-frying process of Hordei Fructus Germinatus on the intestinal absorption of active ingredients in Hordei Fructus Germinatus.

This study was designed to evaluate the absorption promoting capacity of Maillard Reaction Products (MRPs) produced during the stir-frying process of Hordei Fructus Germinatus on catechin, ferulic acid, quercetin and kaempferol by the ex vivo rat everted gut sac model, in situ single-pass intestinal perfusion model and the whole animal model. Moreover, verapamil, EDTA and mannitol were used for determining the transport mechanism of catechin, ferulic acid, quercetin and kaempferol. The tight junction (TJ) proteins including zonula occudens-1(ZO-1) and claudin-1 were chosen to investigate the promoting mechanism of MRPs by quantitative real-time PCR (qRT-PCR) and western blot analyses. The results showed that the MRPs produced during the stir-frying process of Hordei Fructus Germinatus could improve the intestinal absorption of catechin, ferulic acid, quercetin and kaempferol. And the absorption-promoting effect of MRPs was related to chelating effect and the reduced expression of claudin-1 and ZO-1. Our results suggested that MRPs could be promising oral absorption promoters, which might be another processing mechanism of Hordei Fructus Germinatus.

Self-Assembled Micelles Improve the Oral Bioavailability of Dihydromyricetin and Anti-Acute Alcoholism Activity.

Dihydromyricetin (DMY) is highly effective in counteracting acute alcohol intoxication. However, its poor aqueous solubility and permeability lead to the low oral bioavailability and limit its clinic application. The aim of this work is to use Solutol®HS15 (HS 15) as surfactant to develop novel micelle to enhance the oral bioavailability of DMY by improving its solubility and permeability. The DMY-loaded Solutol®HS15 micelles (DMY-Ms) were prepared by the thin-film hydration method. The particle size of DMY-Ms was 13.97 ± 0.82 nm with an acceptable polydispersity index of 0.197 ± 0.015. Upon entrapped in micelles, the solubility of DMY in water was increased more than 25-fold. The DMY-Ms had better sustained release property than that of pure DMY. In single-pass intestinal perfusion models, the absorption rate constant (Ka) and permeability coefficient (Papp) of DMY-Ms were 5.5-fold and 3.0-fold than that of pure DMY, respectively. The relative bioavailability of the DMY-Ms (AUC0-∞) was 205% compared with that of pure DMY (AUC0-∞), indicating potential for clinical application. After administering DMY-Ms, there was much lower blood alcohol level and shorter duration of the loss of righting relax (LORR) in drunk animals compared with that treated by pure DMY. In addition, the oral administration of DMY-Ms greatly reduced oxidative stress, and significantly defended liver and gastric mucosa from alcoholic damages in mice with alcohol-induced tissue injury. Taken together, HS 15-based micelle system greatly improves the bioavailability of DMY and represents a promising strategy for the management of acute alcoholism. Graphical abstract.

Effect of paracellular permeation enhancers on intestinal permeability of two peptide drugs, enalaprilat and hexarelin, in rats

Transcellular permeation enhancers are known to increase the intestinal permeability of enalaprilat, a 349 Da peptide, but not hexarelin (887 Da). The primary aim of this paper was to investigate if paracellular permeability enhancers affected the intestinal permeation of the two peptides. This was investigated using the rat single-pass intestinal perfusion model with concomitant blood sampling. These luminal compositions included two paracellular permeation enhancers, chitosan (5 mg/mL) and ethylenediaminetetraacetate (EDTA, 1 and 5 mg/mL), as well as low luminal tonicity (100 mOsm) with or without lidocaine. Effects were evaluated by the change in lumen-to-blood permeability of hexarelin and enalaprilat, and the blood-to-lumen clearance of 51chromium-labeled EDTA (CLCr-EDTA), a clinical marker for mucosal barrier integrity. The two paracellular permeation enhancers increased the mucosal permeability of both peptide drugs to a similar extent. The data in this study suggests that the potential for paracellular permeability enhancers to increase intestinal absorption of hydrophilic peptides with low molecular mass is greater than for those with transcellular mechanism-of-action. Further, the mucosal blood-to-lumen flux of 51Cr-EDTA was increased by the two paracellular permeation enhancers and by luminal hypotonicity. In contrast, luminal hypotonicity did not affect the lumen-to-blood transport of enalaprilat and hexarelin. This suggests that hypotonicity affects paracellular solute transport primarily in the mucosal crypt region, as this area is protected from luminal contents by a constant water flow from the crypts.

Determination and Comparison of the Solubility, Oil-Water Partition Coefficient, Intestinal Absorption, and Biliary Excretion of Carvedilol Enantiomers.

Carvedilol is administered as a racemic mixture for the therapy of hypertension and heart failure. S-enantiomer is the dominant conformation of pharmacodynamics, but its further development was obstructed by its poor bioavailability. In this study, carvedilol and its enantiomers were compared in terms of solubility, permeability, and biliary excretion, and reasons for the poor bioavailability were discussed. Equilibrium solubility and log P were measured by a shake flask method at a wide pH range (1.2-8.0), and intestinal absorption and biliary excretion were evaluated using a single-pass rat intestinal perfusion model. According to BCS guidance, carvedilol and its R/S enantiomers are considered highly soluble at pH value less than 5.0 and low soluble at neutral or weak alkaline conditions. RS-carvedilol showed significantly lower solubilities at pH1.2-5.0 and higher solubilities at pH6.0-8.0 than its enantiomers. In addition, carvedilol and its enantiomers possessed similar log P values at pH1.2-8.0. High intestinal permeabilities of carvedilol and its enantiomers were observed, and S-carvedilol showed higher absorption than R-carvedilol and RS-carvedilol. The biliary excretion about two major metabolites, 1-hydroxycarvedilol O-glucuronide and 8-hydroxycarvedilol O-glucuronide, of RS-carvedilol, S-carvedilol, and R-carvedilol were 66.4%, 73.5%, and 54.3%, respectively. In conclusion, there are significant differences amongst carvedilol and its R/S enantiomers in terms of solubility, intestine absorption, and biliary excretion abilities. The first pass effect is the primary reasons for the low bioavailability of S-carvedilol. Therefore, pharmaceutical strategies or parenteral routes should be considered to avoid the first pass metabolism.

Panax quinquefolium saponin liposomes prepared by passive drug loading for improving intestinal absorption

Panax quinquefolium saponin (PQS) composed of 45% pseudo-ginsenoside F11 (PF11), is a natural mixture of sterol compounds obtained from the American ginseng plant, having numerous promising benefits for health. However, low solubility and permeability limit the development of PQS as a therapeutic agent for oral administration. In this study, PQS liposomes (PQS-Lips) were prepared by thin layer hydration, an in situ single-pass intestinal perfusion (SPIP) model was used to verify the improvement of membrane permeability of PQS-Lips. PQS-Lips had a high encapsulation efficiency (EE) of 65%∼70%, a particle size about 100.0 nm, and a zeta potential of −60 mV with regular spherical surface. FTIR and DSC showed the PQS in liposomes were amorphous, indicating that hydrogen bonds formed between one or several hydroxyl groups in PQS and C-O group at the phospholipid polar terminal. In addition, PQS-Lips showed sustained release in vitro than PQS at pH 1.2 and pH 6.8, and PQS-Lips had good stability in simulated gastric and intestinal fluid. Then, the absorption rate (K a) and effective permeability coefficient (P eff) of PQS-Lips in the whole small intestine were significantly higher than those in PQS solution (PQS-Sol), which proved that the PQS-Lips could significantly increase the membrane permeability of PQS and promote its absorption in the small intestine. From the experimental results, it could be known that liposome technology could effectively improve the absorption of PQS in the small intestine.