• YAKHAK HOEJI
• /
• v.49 no.2
• /
• pp.185-191
• /
• 2005

The absorption of a P-gp substrate, rhodamine 123, from a liposomal dosage form was investigated across Caco-2 cell monolayers, rat intestines and rat intestinal Peyer's patches in Ussing chamber, Rhodamine 123 was incorporated into liposomes according to the standard evaporation method, which led to a production of liposomes with a mean diameter of 71.3 nm. The permeability (Papp of rhodamine 123 from a water solution across the monolayer was $2.45{\times}10^{-6}$ cm/s for $A{\leftrightarrow}B$ (apical to basal) and $14.0{\times}10^{-6}$ cm/s for $B{\leftrightarrow}A$ (basal to apical) directions, consistent with the fact that rhodamine 123 is one of the P-gp substrates. The transport of rhodamine 123 from the liposomal dosage form was much lower for both directions compared to the solution of rhodamine 123. The transport of rhodamine 123 across the rat intestine was also significantly decreased for both directions, I.e., influx and efflux, by the liposomal incorporation of the compound. The transport of rhodamine 123 across the Peyer's patch was substantially reduced by liposomal incorporation. No difference was found in the transport between the Peyer's patch and non-Peyer's patch. These observations suggest that the contribution of transport via Peyer's patches in the uptake of liposomes may be minimal, especially for rapidly absorbed compounds like rhodamine 123. Therefore, the increased absorption of P-gp substrates does not appear to be feasible by incorporating the compounds in liposomes, due to negligible involvement of Peyer's patches in the uptake of particulate dosage forms like liposomes. Liposomes may rather represent a sustained release dosage form of incorporated compounds.

• Biomolecules & Therapeutics
• /
• v.21 no.2
• /
• pp.173-179
• /
• 2013

Objective of present study was to prepare and characterize self-nanoemulsifying drug delivery system (SNEDDS) of lutein and to evaluate its effect on bioavailability of warfarin. The SNEDDS was prepared using an oil, a surfactant, and co-surfactants with optimal composition based on pseudo-ternary phase diagram. Effect of the SNEDDS on the bioavailability of warfarin was performed using Sprague Dawley rats. Lutein was successfully formulated as SNEDDS for immediate self-emulsification and dissolution by using combination of Peceol as oil, Labrasol as surfactant, and Transcutol-HP or Lutrol-E400 as co-surfactant. Almost complete dissolution was achieved after 15 min while lutein was not detectable from the lutein powder or intra-capsule content of a commercial formulation. SNEDDS formulation of lutein affected bioavailability of warfarin, showing about 10% increase in $C_{max}$ and AUC of the drug in rats while lutein as non-SNEDDS did not alter these parameters. Although exact mechanism is not yet elucidated, it appears that surfactant and co-surfactant used for SNEDDS formulation caused disturbance in the anatomy of small intestinal microvilli, leading to permeability change of the mucosal membrane. Based on this finding, it is suggested that drugs with narrow therapeutic range such as warfarin be administered with caution to avoid undesirable drug interaction due to large amount of surfactants contained in SNEDDS.

• Journal of Dairy Science and Biotechnology
• /
• v.32 no.1
• /
• pp.1-6
• /
• 2014

Probiotics have been extensively studied for their beneficial effects on human health. In particular, Lactobacillus and Bifidobacterium strains have gained considerable attention as major groups of probiotic bacteria that improve gastrointestinal health. However, emerging evidence suggests that probiotics offer benefits beyond those observed in the gut recent studies suggest that probiotics and/or their components exert favorable effects on alcoholic liver disease (ALD) pathogenesis such as decreasing intestinal permeability, inhibiting pathogenic bacteria growth, increasing the activity of alcohol metabolism enzymes, modulating the adaptive immune system, and suppressing fatty acid synthesis genes. In this review, we discuss the results of in vivo and in vitro studies that have examined the use of probiotics to prevent ALD, primarily focusing on those that explore the cellular and molecular mechanisms underlying the activities of promising probiotic strains. The evidence presented in this review could help in screening for probiotic strains that have protective effects in ALD patients and in further elucidating the mechanisms of their actions.

• Mass Spectrometry Letters
• /
• v.9 no.2
• /
• pp.61-65
• /
• 2018

KPLA-012, a benzopyranyl 1,2,3-triazole compound, is considered a potent $HIF-1{\alpha}$ inhibitor based on the chemical library screening, and is known to exhibit anti-angiogenetic and anti-tumor progressive effects. The aim of this study was to investigate the pharmacokinetic properties of KPLA-012 in ICR mice and to investigate in vitro characteristics including the intestinal absorption, distribution, metabolism, and excretion of KPLA-012. The oral bioavailability of KPLA-012 was 33.3% in mice. The pharmacokinetics of KPLA-012 changed in a metabolism-dependent manner, which was evident by the low recovery of parent KPLA-012 from urine and feces and metabolic instability in the liver microsomes. However, KPLA-012 exhibited moderate permeability in Caco-2 cells ($3.1{\times}10^{-6}cm/s$) and the metabolic stability increased in humans compared to that in mice (% remaining after 1 h; 47.4% in humans vs 14.8% in mice). Overall, the results suggest that KPLA-012 might have more effective pharmacokinetic properties in humans than in mice although further studies on its metabolism are necessary.

• Archives of Pharmacal Research
• /
• v.25 no.5
• /
• pp.572-584
• /
• 2002

Rapid development in molecular biology and recent advancement in recombinant technology increase identification and commercialization of potential protein drugs. Traditional forms of administrations for the peptide and protein drugs often rely on their parenteral injection, since the bioavailability of these therapeutic agents is poor when administered nonparenterally. Tremendous efforts by numerous investigators in the world have been put to improve protein formulations and as a result, a few successful formulations have been developed including sustained-release human growth hormone. For a promising protein delivery technology, efficacy and safety are the first requirement to meet. However, these systems still require periodic injection and increase the incidence of patient compliance. The development of an oral dosage form that improves the absorption of peptide and especially protein drugs is the most desirable formulation but one of the greatest challenges in the pharmaceutical field. The major barriers to developing oral formulations for peptides and proteins are metabolic enzymes and impermeable mucosal tissues in the intestine. Furthermore, chemical and conformational instability of protein drugs is not a small issue in protein pharmaceuticals. Conventional pharmaceutical approaches to address these barriers, which have been successful with traditional organic drug molecules, have not been effective for peptide and protein formulations. It is likely that effective oral formulations for peptides and proteins will remain highly compound specific. A number of innovative oral drug delivery approaches have been recently developed, including the drug entrapment within small vesicles or their passage through the intestinal paracellular pathway. This review provides a summary of the novel approaches currently in progress in the protein oral delivery followed by factors affecting protein oral absorption.

• Journal of The Korean Dental Society of Anesthesiology
• /
• v.6 no.2 s.11
• /
• pp.121-126
• /
• 2006

Generalized anaphylaxis is a most dramatic and acutely life-threatening allergic reaction. Most fatalities from anaphylaxis occur within the first 30 minutes postantigenic exposure. The mechanism of generalized anaphylaxis is the reaction of IgE antibodies to an allergen that causes the release of histamine, bradykinin, and others. These chemical mediators cause the contraction of smooth muscles of the respiratory and intestinal tracts, as well as increased vascular permeability. Four major clinical symptoms are recognized: skin reactions, smooth muscle spasm (gastrointestinal and genitourinary tracts and respiratory smooth muscle), respiratory distress, and cardiovascular collapse. Epinephrine is the drug of choice for the management. Its syrnpathomimetic effects directly counteract most aspects of the attack. Respiration must be immediately supported by the establishment of a patent airway along with artificial ventilation. The circulation should be supported and the existing hypotension overcome by placing the victim in a position to allow gravity to aid venous return and by administering intravenous fluids, vasopressors, and corticosteroids. When an imperceptible pulse is evident, external cardiac compression must also be instituted. This is a case report of anaphylactic shock care during general anesthesia, possibly due to penicillin, pancuronium and others.

• The Korean Journal of Physiology
• /
• v.1 no.2
• /
• pp.157-168
• /
• 1967

The entry of antipyrine and urea from the peritoneal cavity of rabbit into organ tissue and blood plasma was studied. Two hundred mg of antipyrine plus 300 mg of urea in 10 ml Ringer's solution was injected into the peritoneal cavity of anesthetized rabbit. The injection was made from above of a rabbit kept tying right side down and it enabled part of the abdominal organs (liver, intestine, kidney) was immersed in the injected solution and kept high concentration gradient throughout the experimental period. The remaining part of the organs was revered only by a thin film of the test solution. Subsequently, in this part of the organs the concentration gradient of the diffusible substances during entry was presumed to decrease as time elapsed. Four pieces of the liver tissue were taken namely, the right superficial, right deep, left superficial and left deep portions. Two were taken from the small intestine, one from the portion which was immersed in. the fluid and the other from that above the fluid mass. Both kidneys were separately analyzed. As a remote organ the gastrocnemius muscle was taken from the right leg of the animal. The intervals which were the time periods elapsed after injections were 5,7,10,15 or 30 minutes. At each point 5 animals were sacrificed and the concentrations of the test substances in the tissue water were measured. The results obtained were as follows. 1. In the liver the right portion which was immersed in the fluid showed higher concentration if the test substances than the left portion and the superficial region exceeded the deep region. The concentrations diminished as the time elapsed after infusion, particulary in the case of antipyrine, suggesting circulatory removal of the substances. In urea such decreasing tendency of the concentration was not obvious, and suggested slower removal rate of it as compared with that of antipyrine. 2. In the small intestine there was no regional difference in the concentration of the test substances. Because of the intestinal motility different portions of the intestine were seemed to have bathed in the fluid of the same concentration. In general the concentrations in the intestinal wall exceeded those of the liver, suggesting a slower removal rate than in the latter. 3. In the kidney the accumulation of the endogenous urea was predominant, and the accumulating mechanism in the renal tissue went on during the period of the experiment. Therefore it revealed increasing tendencies as the time elapsed. The penetration of the test substances in this organ from the peritoneal cavity seemed to be slower than in other abdominal organs, namely liver or small intestine. Part of the test substances in the kidney were obviously brought by the blood stream. 4. Rapid exponential decay of the concentration of antipyrine and of the osmolality of the peritoneal fluid was attributed to the extensive removal through the whole dimension of the peritoneal surface, and the remote organ such as the gastrocnemius muscle attained a fairly close value to that of the abdominal organs in less than 30 minutes. The factors which related to the absorption rate were discussed. They were the concentration gradient, permeability and the regional perfusion rate.

• The Korean Journal of Physiology and Pharmacology
• /
• v.24 no.1
• /
• pp.101-110
• /
• 2020

Transient receptor potential canonical 4 (TRPC4) channel is a nonselective calcium-permeable cation channels. In intestinal smooth muscle cells, TRPC4 currents contribute more than 80% to muscarinic cationic current (mIcat). With its inward-rectifying current-voltage relationship and high calcium permeability, TRPC4 channels permit calcium influx once the channel is opened by muscarinic receptor stimulation. Polyamines are known to inhibit nonselective cation channels that mediate the generation of mIcat. Moreover, it is reported that TRPC4 channels are blocked by the intracellular spermine through electrostatic interaction with glutamate residues (E728, E729). Here, we investigated the correlation between the magnitude of channel inactivation by spermine and the magnitude of channel conductance. We also found additional spermine binding sites in TRPC4. We evaluated channel activity with electrophysiological recordings and revalidated structural significance based on Cryo-EM structure, which was resolved recently. We found that there is no correlation between magnitude of inhibitory action of spermine and magnitude of maximum current of the channel. In intracellular region, TRPC4 attracts spermine at channel periphery by reducing access resistance, and acidic residues contribute to blocking action of intracellular spermine; channel periphery, E649; cytosolic space, D629, D649, and E687.

• Journal of Pharmaceutical Investigation
• /
• v.41 no.4
• /
• pp.239-247
• /
• 2011

Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol. Simvastatin has good permeability, but it also has low solubility (BCS class II), which reduces its bioavailability. To overcome this problem, a solid dispersion is formed using a spray-dryer with polymeric material carrier to potentially enhance the dissolution rate and extend drug absorption. As carriers for solid dispersion, Gelucire$^{(R)}$44/14 and Gelucire$^{(R)}$ 50/13 are semisolid excipients that greatly improve the bioavailability of poorly-soluble drugs. To avoid any toxic effects of an organic solvent, we used aqueous medium to melt Tween$^{(R)}$ 80 and distilled water. The structural behaviors of the raw materials and the solid dispersion were analyzed by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The DSC and PXRD data indicated that the crystalline structure of simvastatin was transformed to an amorphous structure through solid dispersion. Then, solid dispersion-based tablets containing 20 mg simvastatin were prepared with excipients. Dissolution tests were performed in distilled water and artificial intestinal fluid using the USP paddle II method. Compared with that of the commercial tablet (Zocor$^{(R)}$ 20 mg), the release of simvastatin from solid dispersion based-tablet was more efficient. Although the stability study is not complete, this solid dispersion system is expected to deliver poorly water-soluble drugs with enhanced bioavailability and less toxicity.

• Journal of Oriental Neuropsychiatry
• /
• v.31 no.3
• /
• pp.149-156
• /
• 2020

Objectives: The purpose of this study was to experimentally assess the effects of Chengsimyeonjatanggagam extracts in the animal model regarding ADHD related symptoms and indicators. Methods: The experimental group was classified into the normal group (WKY rat) in 7, the control group (SHR rat) in 7, the low-concentration group of herbal medicines (SHR rat) in 7, and the high-concentration group of herbal medicines (SHR rat) in 7 by random sampling. The open field test was conducted three times on the 7th, 14th, and 21st days during the oral medication. After that, Y-maze test, intestinal permeability verification (L/M ratio), and Western blotting (CDK expression in the cerebral cortex) were performed in sequence. Results: The Chengsimyeonjatang-gagam extracts reduced the activity distance in the SHR rat at 21 days in the low and high concentration groups by the open field test. It also reduced the cross-action rate in the low and high concentration groups by the Y-maze test. And the low concentration group showed 52.3% decrease in the L/M ratio compared to the SHR group. Finally, the CDK5 protein significantly increased in the low and high concentration groups. Conclusions: This study suggests that the Chengsimyeonjatang-gagam extracts have potential to be used for the treatment of ADHD.