Upper Part Of Small Intestine Research Articles

Gastroretentive Drug Delivery Systems with improved Floating and Swelling Capabilities

For medications with an absorption window in the stomach and upper part of small intestine, a controlled drug delivery system with a longer stomach residence duration can be particularly useful. Rapid gastrointestinal transit may cause drug delivery system above the absorption zone to only partially release drug, which would reduce the supplied dose's effectiveness. The main drawbacks are linked to the non-uniformity of drug absorption across the alimentary canal and the inter- and intra-subject variability of gastro-intestinal transit time. The bioavailability of medications is predicted to be improved by floating delivery systems, which are designed to stay buoyant on the gastric contents for an extended period of time. Floating in combination with swellable system gaining attention due to their wide applicability in the targeting of drugs to stomach. These floating and swellable tablet have the advantage that they remain buoyant and swells to 2-3 folds in gastric fluid.

Development of Combine Bio-adhesive – Floating Drug Delivery System by using Different Polymer

The goal of designing sustained release drug delivery systems of tablets is to reduce the frequency of dosing or to increase the effectiveness of the drug by localization at the site of action, reducing the dose required, or providing controlled drug delivery. The oral route is considered as the most promising route of drug delivery. Effective oral drug delivery may depend upon the factor such as gastric emptying process, gastrointestinal transit time of dosage form. Most of the oral dosage forms possess several physiological limitations such as variable gastrointestinal transit, because of variable gastric emptying leading to non-uniform absorption profiles, incomplete drug release and shorter residence time of the dosage form in the stomach. This lead to incomplete absorption of drug having absorption window especially upper part of small intestine, as once the drug passes down the absorption site the remaining quantity goes down unabsorbed.

Enhancement of Aqueous Solubility and Oral Bioavailability of Bcs Class II Drug by Dry Emulsion

Liquid emulsions have distinct advantages over other dosage forms by improving oral bioavailability as well as by reducing the side effects. On contrary, liquid emulsion exhibit lack of physicochemical stability and compliance issues. To overcome these problems, dry emulsion formulation recommended. Dry emulsions are formulated by spray drying, evaporation and rotary evaporation. The aim of the present investigation is to improve the dissolution and oral bioavailability of poorly water soluble drug Olmesartan medoxomil by preparing dry emulsion. Olmesartan medoxomil is poorly soluble drug used for treatment of high blood pressure, showing absorption window at stomach and upper part of small intestine. Dry emulsion was ready by victimisation purgative during which drug is very soluble, using poloxamer188 as water soluble carrier and aerosil 200 as an adsorbent. The preferred oils were castor oil, olive oil, soybean oil and isopropyl myristate and polymers were PEG400, Eudragit EPO and Poloxamer 188. Dry emulsion was prepared by spray drying. Dry emulsion was evaluated for drug content, percentage moisture content, aqueous solubility, dissolution study and in-vivo bioavailability study. In vitro drug release of dry emulsion was studied by using USP type II paddle dissolution apparatus. The solubility of the drug was increased with surfactant and polymer at 1:1 ratio. Probable mechanisms of improved solubility were characterized by particle size determination, Differential Scanning Calorimetry (DSC), Powder X-ray Diffractometry (PXRD) and Scanning Electron Microscopy (SEM). This study revealed that solid dry emulsion technique could prove promising for improvement of solubility, dissolution rate and oral bioavailability of Olmesartan medoxomil.

Preparation and in-Vitro Evaluation of Cinnarizine Raft Forming Chewable Tablets

Cinnarizine is an anti-histaminic drug and is mainly used to treat symptoms accompanying motion sickness like vomiting and dizziness. It has low and variable bioavailability due to its low water solubility. Cinnarizine (weakly basic drug) is formulated as raft forming chewable Tablets to allow its complete dissolution at the stomach to be absorbed at the upper part of small intestine. Raft forming chewable Tablets are formulated by direct compression method using sodium alginate or pectin as raft forming agents. The prepared Tablets were evaluated for their pre and post- compression parameters and they have shown desirable results regarding evaluation of hardness, thickness, % friability, weight variation, content uniformity, raft strength, weight and volume, in addition to in-vitro drug release. Out of all the prepared formulas F1 selected as the optimum formula with 488.1mg raft strength and 92.34% drug release after 24hrs that is promising for the formulation of the raft system.

Update on the Molecular Mechanisms Underlying the Effect of Cholecystokinin and Cholecystokinin-1 Receptor on the Formation of Cholesterol Gallstones.

Cholecystokinin (CCK) is an important neuro-intestinal peptide hormone produced by the enteroendocrine I-cells in the upper part of small intestine. Protein- and fat-enriched food plays an important role in triggering CCK secretion from the intestine. Carbohydrates stimulate only small amounts of CCK release. The CCK-1 receptor (CCK-1R) is largely localized in the gallbladder, sphincter of Oddi, pancreas, small intestine, gastric mucosa, and pyloric sphincter, where it is responsible for CCK to regulate multiple digestive processes including gallbladder contraction, pancreatic secretion, small intestinal transit, and gastric emptying. Accumulated evidence clearly demonstrates that CCK regulates gallbladder and small intestinal motility through CCK-1R signaling cascade and the effect of CCK-1R on small intestinal transit is a physiological response for regulating intestinal cholesterol absorption. Disruption of the Cck or the Cck-1r gene in mice significantly increases the formation of cholesterol gallstones by disrupting gallbladder emptying and biliary cholesterol metabolism, as well as promoting intestinal absorption of cholesterol. Abnormalities in gallbladder motility function in response to exogenously administered CCK are found primarily in patients with cholesterol gallstones. Patients with pigment gallstones display an intermediate degree of gallbladder motility defect without gallbladder inflammation and enlarged fasting gallbladder. Dysfunctional gallbladder contractility has been found under several conditions such as pregnancy, obesity, diabetes, celiac disease, and total parenteral nutrition although gallstones are not observed. The gallbladder-specific CCK-1R-selective agonist may lead to an efficacious novel way for preventing gallstone formation by promoting gallbladder emptying, particularly for pregnant women and subjects with dysfunctional gallbladder motility function such as celiac patients, as well as patients with total parenteral nutrition.

Preparation and in-Vitro Evaluation of Cinnarizine Raft Forming Chewable Tablets

Cinnarizine is an anti-histaminic drug and is mainly used to treat symptoms accompanying motion sickness like vomiting and dizziness. It has low and variable bioavailability due to its low water solubility. Cinnarizine (weakly basic drug) is formulated as raft forming
 
 chewable Tablets to allow its complete dissolution at the stomach to be absorbed at the upper part of small intestine. Raft forming chewable Tablets are formulated by direct compression method using sodium alginate or pectin as raft forming agents. The prepared Tablets were evaluated for their pre and post- compression parameters and they have shown desirable results regarding evaluation of hardness, thickness, % friability, weight variation, content uniformity, raft strength, weight and volume, in addition to in-vitro drug release. Out of all the prepared formulas F1 selected as the optimum formula with 488.1mg raft strength and 92.34% drug release after 24hrs that is promising for the formulation of the raft system.
 Cinnarizine is an anti-histaminic drug and is mainly used to treat symptoms accompanying motion sickness like vomiting and dizziness. It has low and variable bioavailability due to its low water solubility. Cinnarizine (weakly basic drug) is formulated as raft forming
 
 chewable Tablets to allow its complete dissolution at the stomach to be absorbed at the upper part of small intestine. Raft forming chewable Tablets are formulated by direct compression method using sodium alginate or pectin as raft forming agents. The prepared Tablets were evaluated for their pre and post- compression parameters and they have shown desirable results regarding evaluation of hardness, thickness, % friability, weight variation, content uniformity, raft strength, weight and volume, in addition to in-vitro drug release. Out of all the prepared formulas F1 selected as the optimum formula with 488.1mg raft strength and 92.34% drug release after 24hrs that is promising for the formulation of the raft system.

Effect of mucus layer on the transcellular absorption of lipophilic drugs in rat small intestine

PurposeThe mucus layer, which is adjacent to the intestinal wall, is considered to be a physiological barrier to intestinal drug absorption, since a drug must diffuse through this lipophilic layer prior to permeation across the intestinal epithelial cells. Thus, mucus layer permeation is suggested to be a rate‐limiting step in the intestinal absorption of lipophilic drugs. The major glycoprotein components of the mucus layer are mucins, which presumably play a pharmaceutical role in intestinal drug absorption, however, there have been no reports that describe the contribution of mucins to intestinal drug absorption at the molecular level. In this study, we examined the involvement of the mucus layer in the intestinal permeability of various lipophilic drugs in rat small intestine. Furthermore, we evaluated the regional distributions of mucins (MUCs) in rat gastrointestinal tract and explored the relationship between the effect of the mucus layer on passive transcellular transport and the expression pattern of mucins.MethodsDrug permeation experiments were conducted using the in vitro sac method. The amount of mucus glycoproteins liberated from the intestinal wall were determined by the alcian blue method. The mRNA and protein expression levels of mucins were evaluated by quantitative real‐time RT‐PCR (qPCR) and Western blotting, respectively.Results and DiscussionThe membrane permeability of the lipophilic drugs in the rat gastrointestinal tract was increased by pretreatment with dithiothreitol (DTT), which is commonly used as a mucus remover, and the alternation was remarkable in the upper part of the small intestine. Furthermore, the enhancing effects of DTT tended to be pronounced on the permeability of drugs with higher log D values in the case of neutral drugs with non‐dissociable groups. These results indicated that the effect of the mucus layer on intestinal permeability depends on the log D values and the physiological charge of the compound. On the other hand, the mRNA expression analysis of MUC genes revealed that the intestinal expression of MUC5AC is considerably higher in the duodenum, and those of MUC1, MUC2, and MUC3A are gradually increased toward the lower intestine in rats. Furthermore, Western blotting showed abundant MUC5AC protein in the mucus solution liberated from jejunum, but not from ileum and colon by the treatment with DTT. Therefore, these results suggest that rMUC5AC is involved in the absorption of lipophilic drugs in the upper part of rat small intestine.ConclusionsMUC5AC could be involved in the barrier function to limit the transcellular permeation of hydrophobic drugs in the upper part of the gastrointestinal tract.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Evaluation of In Vivo Transfection Efficiency of Eudragit Coated Nanoparticles of Chitosan-DNA: A pH-sensitive System Prepared for Oral DNA Delivery

Background:Success of any gene therapy protocol relies mostly on using an efficient carrier to direct nucleic acid to the place of action. The system should also have transfection ability at release site. Different routes are available for delivering genetic materials to the target organs, amongst them; oral delivery is particularly attractive for certain reasons. However, serious obstacles, like acidic environment of stomach and presence of protease and nuclease enzymes in gastrointestinal (GI) tract, make oral route a highly challenging option.Objectives:The present study suggests preparation of gene nanoparticles (NPs) of chitosan within a layer of Eudragit L100 for oral delivery of nucleic acid. The nanoparticles have some features both in size and polymer properties that can be penetrating enough to transfect epithelial layer cells of intestine and protect the entrapped materials against stomach harsh condition.Materials and Methods:In this experimental study, conducted in Iran, particles were prepared by coacervation technique followed by encapsulation of nanoparticle within a coat of Eudragit L100 using solvent evaporation technique. Formulation behavior was monitored both in vitro and in vivo. Stability of particle construction and release profile of DNA were examined at pH of ± 0.8 environ pKa of Eudragit. Size and zeta potential of particles were measured. To demonstrate transfection efficiency of the constructed carrier, reverse transcription polymerase chain reaction (RT-PCR) was carried out using human insulin specific primers on total RNA extracted from upper part of small intestine of 48-hour post-transfected rats (sampled by simple random selection, n = 3).Results:The mean size and zeta potential of particles were 300 ± 4 nm and 14 ± 0.5 mV, respectively. Encapsulation of this system was 89.6 ± 1.2%. DNA release from batches was less than 12% at pH = 5.2 and more than 60% at pH = 6.8 with significant difference of P < 0.05. RT-PCR product confirmed the presence of insulin transcript of 437 bp in upper intestinal extracts of the transfected rats. No band of DNA was seen after RT-PCR of placebo form of nanoparticles received group.Conclusions:Eudragit coated nanoparticle of chitosan is an efficient choice for oral delivery of DNA to upper part of GI tract.

English

Oral administration has only limited use for important drugs from various pharmacological categories, that have poor oral bio-availability due to incomplete absorption and/or degradation in the gastrointestinal tract (GIT). Drugs that are easily absorbed from the gastrointestinal tract (GIT) and have a short half-life are eliminated quickly from the blood circulation, so they require frequent dosing. To avoid this drawback, the oral sustained-controlled release formulations have been developed in an attempt to release the drug slowly into the gastrointestinal tract (GIT) and maintain an effective drug concentration in the serum for longer period of time. However, such oral drug delivery devices have a physiological limitation of gastric retention time (GRT), variable and short gastric emptying time can result in incomplete drug release from the drug delivery system (DDS) in the absorption zone (stomach or upper part of small intestine), leading to diminished efficacy of the administered dose. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration. This idealized objective points to the two aspects most important to the drug delivery; namely spatial placement and temporal delivery of a drug. Spatialplacement relates to targeting a drug to a specific organ or a tissue while temporal delivery refers to controlling the rate of drug delivery to that specific organ or a Tissue. Key words: Gastroretentive, drugdelivery, controlled.

Improving the therapeutic efficiency of ginger extract for treatment of colon cancer using a suitably designed multiparticulate system

Ginger extract (GE), a potential natural anticancer agent, has compromised therapeutic utilization due to poor bioavailability and physicochemical properties. Present study aimed at assigning GE with a pharmaceutical couture so as to improve its biopharmaceutical performance by monitoring its localized (though prolonged) delivery in the distal parts of gastrointestinal tract for the treatment of colon cancer. Alginate beads entrapping 85.9 ± 1.78% GE were subjected to Eudragit S100 coating. Latter is insoluble at acidic and near neutral (6.8) pH of stomach and upper part of small intestine and it led to 50% retardation (upto 12 h) in release of GE. However, it was solubilised at pH > 7.0 resulting in colon targeted system. Developed beads were free flowing, showed a particle size of 0.9 ± 0.006 mm and super class-II release controlled by swelling and polymer relaxation. Preclinical evaluation using 1,2-dimethylhydrazine-induced colon cancer, in male Wistar rats, in terms of histopathology, oxidative stress, mitochondrial complex activity, β-glucuronidase and ammonia concentration determinations indicated GE loaded beads (50 mg/kg) to be significantly better (p < 0.05) than free GE. Highlight of the study was that GE loaded coated alginate beads were administered after the induction of colon cancer and significant recession of the cancers was observed after 4 weeks of treatment.

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

To investigate the mechanisms underlying the intestinal absorption of the major bioactive component forsythoside A (FTA) extracted from Forsythiae fructus. An in vitro Caco-2 cell model and a single-pass intestinal perfusion in situ model in SD rats were used. In the in vitro Caco-2 cell model, the mean apparent permeability value (P(app)-value) was 4.15×10(-7) cm/s in the apical-to-basolateral (AP-BL) direction. At the concentrations of 2.6-10.4 μg/mL, the efflux ratio of FTA in the bi-directional transport experiments was approximately 1.00. After the transport, >96% of the apically loaded FTA was retained on the apical side, while >97% of the basolaterally loaded FTA was retained on the basolateral side. The P(app)-values of FTA were inversely correlated with the transepithelial electrical resistance. The paracellular permeability enhancers sodium caprate and EDTA, the P-gp inhibitor verapamil and the multidrug resistance related protein (MRP) inhibitors cyclosporine and MK571 could concentration-dependently increase the Papp-values, while the uptake (OATP) transporter inhibitors diclofenac sodium and indomethacin could concentration-dependently decrease the P(app)-values. The intake transporter SGLT1 inhibitor mannitol did not cause significant change in the P(app)-values. In the in situ intestinal perfusion model, both the absorption rate constant (K(a)) and the effective permeability (P(eff)-values) following perfusion of FTA 2.6, 5.2 and 10.4 μg/mL via the duodenum, jejunum and ileum had no significant difference, although the values were slightly higher for the duodenum as compared to those in the jejunum and ileum. The low, medium and high concentrations of verapamil caused the largest increase in the P(eff)-values for duodenum, jejunum and ileum, respectively. Sodium caprate, EDTA and cyclosporine resulted in concentration-dependent increase in the P(eff)-values. Diclofenac sodium and indomethacin caused concentration-dependent decrease in the Peff-values. Mannitol did not cause significant change in the P(app)-values for the duodenum, jejunum or ileum. The results suggest that the intestinal absorption of FTA may occur through passive diffusion, and the predominant absorption site may be in the upper part of small intestine. Paracellular transport route is also involved. P-gp, MRPs and OATP may participate in the absorption of FTA in the intestine. The low permeability of FTA contributes to its low oral bioavailability.

In vitro and in vivo evaluation of floating riboflavin pellets developed using the melt pelletization process

Floating pellets were prepared using the melt pelletization process in a Mi-Pro ® high shear mixer (Pro-C-epT, Belgium). Formulations were based on a mixture of Compritol ® and Precirol ® as meltable binders and on the use of sodium bicarbonate and tartaric acid as gas-generating agents. Good floating abilities were obtained by using the gas-generating agents in both the inner matrix and the outer coating layer of the pellets. In vitro evaluation of floating capability was performed both by using the resultant weight apparatus and by counting floating pellets at the surface of beakers containing 0.1N HCl solution, in vivo evaluation of floating pellets capabilities was also performed. Riboflavin-containing floating pellets (FRF) were administered orally to nine healthy volunteers versus non-floating pellets (NFRF). Volunteers were divided in two groups, fasted group ( n = 4) 729 kcal and fed group ( n = 5) 1634 kcal as the total calorie intake on the testing day. An increase of urinary excretion of riboflavin was observed when the volunteers were dosed with the floating pellets, especially after feeding. As riboflavin has a narrow window of absorption in the upper part of small intestine, this phenomenon could be attributable to the gastric retention of floating pellets.

EFFECT OF P-GLYCOPROTEIN ON INTESTINAL ABSORPTION AND BRAIN PENETRATION OF ANTIALLERGIC AGENT BEPOTASTINE BESILATE

The antiallergic agent bepotastine besilate is a nonsedating, second-generation H1-antagonist with high oral absorption and negligible distribution into brain. To clarify the role of P-glycoprotein (P-gp) in the pharmacokinetics of bepotastine, intestinal absorption and brain penetration studies were performed. [(14)C]Bepotastine transport in P-gp-overexpressed LLC-PK1 cells indicated that bepotastine was a substrate of P-gp. The affinity of bepotastine to P-gp estimated by ATPase activity assay was low, with a K(m) value of 1.25 mM. After i.v. administration, the brain/plasma free concentration ratio in mdr1-knockout mice was 3 times higher than that in wild-type mice. The in situ intestinal absorption studies of [(14)C]bepotastine in rats showed a clear regional difference, showing highest permeability at the upper part of small intestine with a decreasing permeability in the descending part of small intestine. The apparent absorption rate constant (ka) of [(14)C]bepotastine in the small intestine was greatly increased by cyclosporin A and verapamil, especially in the distal portion, and the site-specific absorption of [(14)C]bepotastine disappeared. The concentration dependence of ka of [(14)C]bepotastine was observed with a higher ka at higher concentration (20 mM) compared with that at lower concentration (1 microM). In conclusion, bepotastine is a substrate for P-gp, and P-gp clearly limited the brain distribution of bepotastine, whereas the effect of P-gp on intestinal absorption of bepotastine was minimal, presumably because of high membrane permeability at the upper region of small intestine where P-gp is less expressed. Such intestinal absorption property of bepotastine is distinctly different from the low membrane-permeable P-gp substrate fexofenadine.

In vitro and in vivo evaluation in healthy human volunteers of floating riboflavin minitablets

This work relates to sustained-release floating minitablets which are able to float on the surface of aqueous fluids for an extended period of time. Firstly, granules were prepared by melt granulation and then, compressed into minitablets to obtain a multiple-unit system. Formulations were based on the use of a meltable binder, a swellable hydrocolloid and on a mixture of gas-generating agents. In vitro and in vivo evaluations of floating capability were performed. To assess the usefulness of the intragastric buoyancy properties of the floating minitablets (FMT), non-floating minitablets (NFMT) with in vitro riboflavin (RF) release profiles equivalent to the FMT were prepared. FMT and NFMT were administered orally to nine healthy volunteers. The volunteers were divided into two groups, a fasted group (n =5) and a fed group (n =4). The pharmacokinetic parameters were investigated by analysis of riboflavin urinary excretion leading to the observation that the mean amount of riboflavin excreted in the urine seemed to increase when FMT were administered after a meal, but did not increase when NFMT were administered. As riboflavin has a narrow absorption window in the upper part of small intestine, this phenomenon could be attributed to gastric retention of the floating minitablets.

A More Relevant Dissolution Method for Evaluation of Floating Drug Delivery System

Introduction A modified release drug delivery system with prolonged residence time in the stomach is of particular interest for drugs: (a) that are locally acting in the stomach, (b) that have an absorption window in the stomach or in the upper part of small intestine, (c) that are unstable in the intestinal or colonic environments, or (d) have low solubility at high pH values. Systems that prolong the gastric residence time can also be used as sustained release devices with a reduced frequency of administration and therefore, can improve patient compliance (1). Approaches to increase gastric residence time include: (a) bioadhesive delivery systems that adhere to mucosal surfaces, (b) delivery systems that increase in size to retard passage through the pylorus, and (c) density-controlled delivery systems, that either float or sink in gastric fluids (2-6). In vitro dissolution testing is generally carried out for quality control purposes and to establish an in vivo in vitro correlation. Traditional in vitro dissolution methods have been shown to be poor predictors of in vivo performance for floating dosage forms (7).The currently used in vitro dissolution methods do not mimic the conditions present in the stomach. Researchers around the world have tried different methods for studying in vitro dissolution for floating drug delivery systems (8,9). However, each of the methods has some limitations. Hence, a modified in-vitro dissolution method was evaluated.

DIFFERENTIAL EXPRESSION OF TRANSPORTERS IN THE INTESTINE AND ITS APPLICATION TO REGULATION OF THE DRUG ABSORPTION

The present study was aimed to quantify the expression of mRNA of drugt ransporters, including PepT1, mrp2 and mdr1a in the small intestine and to examine the correlations between the expression and the transport activity. Variation in expression levels of transporters along the proximal-distal axis of the intestine was examined. Small intestine of starved and fed rats were removed and divided in eight segments and total RNAs isolated. In fed rats, yield of total RNA was constant among each segment, while the increase was observed in the upper part of small intestine of starved rats. Complementary DNA was prepared by reverse transcription of total RNA of each segment and real-time PCR was performed to quantify mRNA expression of various drug transporters. Expression of PepT1 mRNA was lower in upper segment than that in lower segment. In starved rats, PepT1 expression was increased significantly in the middle part of the intestine. As for mrp2, the expression was higher in upper segment and lower in lower segment and the increase in the expression by the starvation was observed in each segment of the intestine. The mdr1a expression was increased gradually along the proximal-distal axis of the small intestine and there was no difference between starved and fed rats. The actual number of PepT1 mRNA expressed in each segment was approximately 10-fold greater than that of mrp2 or mdrla. The intestinal absorption of cefadroxil (CDX) in each segment at pH6.0 was measured using Ussing chamber. Permeability coefficient of CDX was higher in the ileum and lower in the duodenum. In the starved rat, permeability coefficient of CDX in jejunum was significantly increased compared to fed rats. There was good correlation between PepT1 mRNA expression level and permeability coefficient of CDX under both fed and starved conditions. It is suggested that change in physiological and/or pharmacological state of the intestinal tissue may affect the expression and function of various transporters and thereby altars disposition of drugs.

Use of everted sacs of mouse small intestine as enzyme sources for the study of drug oxidation activities in vitro

1. The use of everted sacs of the small intestine as an enzyme source for the study of the first-pass metabolism of xenobiotics by cytochrome P450s (P450, CYP) is described. Several drug oxidation activities for testosterone, chlorzoxazone, tolbutamide, bufuralol and warfarin were observed when everted sacs (1-cm segment) from different parts ofmouse small intestine were incubated with an NADPH-generating system and each substrate. 2. Most of the drug hydroxylase activities resided in the upper part of mouse small intestine and these activities were much higher than those of intestinal microsomes. Drug oxidation activities decreased along the distance from the upper part of the small intestine except for warfarin hydroxylation. 3. Testosterone 6β-hydroxylation in the everted sacs exhibited the highest catalytic activities among the drug oxidations tested here. In the upper part of the small intestine, thetestosterone 6β-hydroxylase activities of everted sacs subjected once to freezing and thawing were substantially decreased compared with the untreated everted sacs. 4. Testosterone 6β-hydroxylase activities in the everted sacs of the small intestine were significantly inhibited by ketoconazole. Immunoreactive proteins using anti-CYP3A antibodies were detected in the upper and middle parts of the small intestine. 5. The results demonstrated that the upper part of the mouse small intestine serves as the major site for intestinal P450 mediated first-pass metabolism. Everted sacs of the small intestine are therefore useful for the study of drug metabolism as well as of transport and absorption.

ABO Antigens in Red Cells and Digestive Organs of Non-human Primates

Blood group A, B and H antigens on red cells of non-human primates were examined by direct hemagglutination reaction, antibody absorption and heat elution tests. ABH substances on red cells from prosimians, New World and Old World monkeys were detected only by elution test with human anti-A, anti-B and chicken immune anti-H antibodies and their activities were equivalent to those from variants of human group A and B. Red cells of apes except gorilla were agglutinated with anti-A, -B and -H from human antisera, monoclonal antibodies and lectins, and their activities corresponded to the activities of human intermediate types of blood group A and B. Red cells of gorilla reacted weakly with human antisera, but failed to react with monoclonal antibodies, and such reactivities of red cells were corresponded to those of human subgroups.In various species of non-human primates, as in human, blood group specific anti-A and/or -B antibodies were present in the serum according to Landsteiner's rule. Water soluble and chloroform-methanol soluble extracts from digestive tissues of prosimians, New World and Old World monkeys showed the ABH-activities demonstrated on red cell. Extracts from submaxillary glands, stomach and upper part of small intestine showed stronger activities than lower part of intestine, and were almost equivalent to those of tissues from human secretors.

Intestinal absorption mechanisms of gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417) and thyrotropin-releasing hormone (TRH).

The absorption mechanisms of gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417) and thyrotropin-releasing hormone (TRH) were studied in the rat. In situ absorption experiments were carried out by the radioimmunoassay, and experiments using everted sacs of small intestine were by radioactivity measurements with 14C-labeled DN-1417 or 3H-labeled TRH in the low concentration range of drug and by a high pressure liquid chromatography in the rather high concentration range of drug. The site specificity of absorption in the small intestine of rats could not be found with DN-1417, whereas TRH-T was absorbed from only the upper part of small intestine. Dose-proportional absorption of DN-1417 was observed in experiments of in situ as well as in vitro. Dose-proportional transfer of DN-1417 through the everted small intestine was also found within the concentration range from 120 ng/ml to 27 mg/ml, whereas the transfer ratio of TRH decreased with increase in the concentration of TRH. DN-1417 transfer from mucosal to serosal fluid was not inhibited by the replacement of medium Na ions by K ions, pretreatment of intestinal mucosa with HgCl2, the existence of an oligopeptide, or the existence of beta-lactam antibiotics which had been reported to be absorbed by active transport or carrier-mediated transport systems. While, TRH transfer was inhibited by the replacement of medium Na ions by K ions, pretreatment of intestinal mucosa with HgCl2, the existence of an oligopeptide, and the existence of beta-lactam antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)