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@#In order to reveal the intestinal absorption mechanism of saikosaponin d (SSd) in vitro and in vivo, the current research investigated the effects of different experimental conditions (time, concentration, temperature, pH, intestinal segments), transporter inhibitors, paracellular pathway enhancer, metabolic enzyme inhibitors on the intestinal absorption of SSd, in Caco-2 monolayers and a single pass perfusion model in rats.The results showed that the apparent permeability coefficient (Papp) and effective permeability coefficient (Peff) of SSd were 4.75 × 10-7 - 6.38 × 10-7 cm/s and 0.19 × 10-4- 0.27 × 10-4 cm/s, respectively, indicating that it was a low permeability compound, and that the transmembrane transport of SSd was concentration-dependent (0.5-5 μmol/L) and time-dependent (0-180 min).Ileum was the main absorption site for SSd. Experimental results based on Caco-2 monolayers showed that the P-gp inhibitor and paracellular permeability enhancer significantly increased the absorption of SSd (P < 0.05), which was consistent with the results obtained in rats. Inhibitors of OATPs and OCTs showed different results in vitro and in vivo, which may be related to the lower expression of them in jejunum.In summary, the intestinal absorption of SSd occurs through a carrier-mediated and energy-dependent transport, as well as passive diffusion, and P-glycoprotein plays an important role in the active transport of SSd.
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Aim To investigate the absorption characteristics of gallic acid in the intestine, and to provide a theoretical basis for improving the bioavailability of tannins. Methods Single-pass intestinal perfusion (SPIP) model was used for rat in situ and HPLC to determine the concentration of gallic acid. The absorption rate constant Ka and effective apparent permeability coefficient Peff of gallic acid in each intestinal segment were calculated. The effects of different intestinal segments, drug concentrations, pH value, P-glycoprotein (P-gp), and multidrug resistance protein2 (MRP2) on intestinal absorption were assessed. Results The absorption rate constant (Ka) of gallic acid decreased following the sequence of jejunum > duodenum > ileum ≈ colon. With the increase of drug concentration, there was no significant difference in the absorption of gallic acid. The acidic environment (pH 5. 5) was conducive to the absorption of gallic acid. After the addition of P-gp and MRP2 inhibitors, the absorption of gallic acid was significantly different from that without P-gp and MRP2 inhibitors (P < 0. 05). Conclusions Gallic acid can be well absorbed in the intestine of rats, and is best absorbed in jejunum. The absorption mechanism is determined to be passive diffusion. The gallic acid absorption process is affected by the efflux of P-gp and MRP2, which may be the P-gp and MRP2 substrates.
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To determine the absorption properties and study the intestinal absorption kinetics of poncidin in rats. In situ single pass perfusion model was combined with High Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS/MS) method to investigate the intestinal absorption characteristics and calculate absorption parameters with aspects of drug absorption, concentration and perfusion medium. The absorption of poncidin under acid condition at pH 6.5 was more stable, where intestinal enzymes showed little influence on metabolism, and the absorption was significantly higher than that in pH alkaline condition at pH 8.0 (<0.05). Drug concentrations had no significant influence on absorption rate constant of the same intestinal segment Ka and apparent permeability coefficient Papp values of poncidin. Different concentrations of poncidin showed no significant differences in the Ka and Papp values among duodenum, jejunum and colon, but the values were significantly lower than ileum absorption parameters, with significant differences (<0.05). There was no significant effect of verapamil on intestinal absorption of poncidin. The results showed that poncidin could be absorbed at all the studied intestinal segments while ileum seemed to be the best absorption segment in the concentration range of 10-1 000 μg·L⁻¹. The absorption was characterized by a linear dynamic process of passive transport, without absorption saturation. Weak acid environment was helpful for the intestinal absorption of poncidin, and ponicidin was not a substrate of P-glycoprotein (P-gp).
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At present,the study of intestinal absorption of oral drugs mainly includes in vitro,in vivo and in situ methods.In view of the advantages of in situ intestinal perfusion such as simple operation,mature technology,controllable,ensure the neuroendocrine regulation and blood supply,and so on,which could better reflect the true situation of drug absorption.In this study,the research methods and characteristics of intestinal absorption of oral drugs were systematically introduced.The recirculating perfusion method and single-pass perfusion method were compared,and several volume correction methods were also introduced.In order to ensure the operability and accuracy of experimental results,proper experiment method of intestinal absorption will be adopt according to the factors such as drug characters,experiment requirements,experimental conditions,and so on.The article provides a scientific basis for the development of pharmaceutical dosage and clinical rational drug use.
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To investigate the changes in intestinal absorption of ginsenosides Rg₁, ginsenosides Re and ginsenosides Rd after combined administration of Ginseng Radix et Rhizoma extract and Acori Tatarinowii Rhizoma, in order to confirm whether the combined administration is scientific and rational, and provide experimental basis for pharmaceutical studies of the formula. An in vivo single-pass perfusion method was performed to study the effect of various concentrations of ginsenosides Rg₁, ginsenosides Re, ginsenosides Rd on the intestinal absorption at duodenum, jejunum, ileum and colon. The concentrations of ginsenosides Rg₁, ginsenosides Re, ginsenosides Rd were determined by RP-HPLC.The absorption rate constant (Ka) and the apparent absorption coefficient(Papp) of ginsenosides Rg₁, ginsenosides Re, ginsenosides Rd were calculated.The result showed that ginsenosides Rg₁, ginsenosides Re, ginsenosides Rd had a high absorption rate on upper portion of the small intestine. The drug concentration had not significantly impact on the absorption rate, suggesting that ginsenosides Rg₁, ginsenosides Re, ginsenosides Rd were absorbed via passive diffusion.Volatile oil of Acori Tatarinowii Rhizoma had obvious effect in enhancing intestinal absorption of ginsenosides Rg₁, ginsenosides Re, ginsenosides Rd, indicating that the combined administration of Ginseng extract and Acorus tatarinowii Schott is scientific and rational.
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To study the in vivo intestinal absorption kinetics of phloridzin in rats. The absorption of phloridzin in the small intestines and colon of rats was investigated using an in vivo single-pass perfusion method and the drug concentration was measured by HPLC. The effects on intestinal absorption of different drug concentration and P-glycoprotein (P-gp) inhibitor were conducted. The results showed that the phloridzin could be absorbed in whole intestine, but more fully in the jejunum and colon segment,poorly absorbed in the duodenum and ileum. The absorption rate constant (Ka) and the apparent absorption coefficient（Papp）of phloridzin decreased following the sequence of jejunum> colon > duodenum > ileum. Absorption parameters of phloridzin had no significant difference at different concentration (5.14, 10.28, 20.56 mg•L⁻¹) . The saturate phenomena was not observed under the test range of drug concentration, and the absorption mechanism may be the passive diffusion transport.There had a significant difference in Ka and Papp values between P-gp inhibitor and no P-gp inhibitor groups. Phloridzin may be the substrate of P-gp.
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Aim To study the absorption kinetics of se-ries molecular weight 5-ASA-mPEG in rats intestine. Methods The in situ intestinal absorption property of 5-ASA-mPEG in rats was investigated by means of sin-gle-pass perfusion, and HPLC method was established to determine the drug concentration in the perfusate. Results The drug concentration and the site of intes-tine segments had little effect on the drug absorption constant ( Ka ) and apparent absorption coefficient (Papp). The perfusion flow rate and the variable mo-lecular weight of 5-ASA-mPEG could significantly af-fect the Ka and Papp. Conclusion 5-ASA-mPEG can be absorbed at all segments of the intestine of rats and has no specific absorption site. It is preliminarily in-ferred that the absorption mechanism of 5-ASA-mPEG is passive transportation. The intestinal absorption of 5-ASA-mPEG shows a downward trend with the increase in molecular weight. The results shows that the modifi-cation of 5-ASA by PEG can effectively inhibit the in-testinal absorption of mesalazine.
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Objective: To investigate the intestinal absorption characteristics of five kinds of flavonoids from Hedyotis diffusa extract in rats. Methods: The in situ rat single-pass intestinal perfusion model was used. The contents of rutin, isoquercitrin, quercetin, kaempferol, and quercetin in perfusates were determined by HPLC-DAD, and the rat intestinal absorption parameters of flavonoids were calculated. Results: In perfusion model, the effective permeability coefficients (Peff) of all components were low. The absorption rate constant (Ka) and Peff had no significant difference when the concentration of total flavonoids from H. diffusa was 0.5-4.0 g/L. In the 2.0 g/L concentration, Ka of rutin, isoquercitrin, quercetin, kaempferol, and quercetin were 0.0113, 0.0154, 0.0102, 0.0305, and 0.0275 min-1, respectively; The Ka sequences of rutin and isoquercitrin in different intestinal segments were ileum > duodenum > jejunum ≈ colon and jejunum > duodenum > ileum ≈ colon. Conclusion: The absorption of the five flavonoids from H. diffusae is a first-order process with the passive diffusion mechanism. The absorption rates of each flavonoid are significantly different. The absorption rate of flavonoid glycosides is lower than that of aglycones. The flavonoids from H. diffusa could be absorbed in all the intestinal segments. The best parts of intestine to absorb rutin and isoquercitrin are ileum and jejunum.
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Objective: To investigate the intestinal absorption characteristics of α-hederin and to explore the causes of poor bioavailability. Methods: In vivo single-pass perfusion model was used and the concentration of α-hederin was determined by HPLC. The effects of intestinal segment, drug concentration, pH value, gut microflora, and P-gp inhibitor on the intestinal absorption of the drug were investigated. Results: The absorption rate constant (Ka) of α-hederin decreased following the sequence of ileum > colon > jejunum > duodenum. Absorption parameters of α-hederin had no significant difference at different concentration of 75, 150, and 300 μg/mL and those increased with the increase of pH value. The intestinal flora which were disrupted may affect the absorption of α-hederin. There was no significant difference in Ka and Peff values between P-gp inhibitor and no P-gp inhibitor groups. Conclusion: α-Hederin can be absorbed in whole intestine, but better in lower intestine. The saturate phenomena was not observed under the test range of drug concentration, and the absorption mechanism may be the passive diffusion transport. The absorption can be better under basic condition. The absorption is significantly affected by the intestinal flora and α-hederin is not the substrate of P-gp.
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OBJECTIVE: To prepare gossypol nanosuspensions and investigate their physicochemical properties and intestinal absorption behavior in rats. METHODS: Gossypol nanosuspensions were prepared by a high pressure homogenization method. Nanosuspensions' characteristics were investigated from particle size distribution, Zeta potential, particle morphology, crystal physical state, storage stability, saturation solubility, and in vitro release. Nanosuspensions' intestinal absorption characteristics were also observed in rats. RESULTS: The nanosuspensions existed as uniform rods. The mean particle size was (217±23) nm, and Zeta potential was -22.7 mV. Gossypol existed in crystalline form. Long-term stability test showed that gossypol nanosuspensions were stable at 4°C for 3 months. The experiment of intestinal absorption showed that the nanosuspensions could be absorbed through passive diffusion with significant variation at different sections. The experiment also showed that the absorption process was not affected by the efflux of P-glyco-protein (drug efflux pump). CONCLUSION: Gossypol nanosuspensions are successfully developed. The solubility in water and the release in vitro of the nanosuspensions are enhanced compared with the bulk drug of gossypol. This study provides a reference for the further pharmaceutical study of gossypol.
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OBJECTIVE: To prepare a new puerarin self-microemulsion to reduce the toxicity of traditional self-microemulsion and maintain the characteristics in vitro and in vivo.
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OBJECTIVE: To investigate the absorption characteristics of dauricine in rat intestine. METHODS: In situ single-pass perfusion model was used and the concentrations of dauricine in perfusate were determined by HPLC. The effects of perfusion rates, intestinal segments and drug concentrations on the intestinal absorption of dauricine were studied. RESULTS: The absorption rate and absorption degree of dauricine increased with the perfusion rates(0.1, 0.2 and 0.4 mL · min-1)(P0.05); at high, middle and low concentrations, the drug absorption rate constants(Ka) were (2.36±0.0073) × 10-2, (3.73 ± 0.0052) × 10-2 and(5.62 ± 0.0136) × 10-2 min-1, respectively, the apparent permeation coefficients(P.,) were(2.02±0.0002) × 103, (3.10±0.0007) × 10-3 and (5.31±0.0010) × 10-3 cm · min-1, respectively, the absorption percentages(P%) were 8.66%, 10.17% and 19.06%, respectively, and the accumulate absorption amount and accumulate absorption percentages of different concentrations at different time were very low. CONCLUSION: The absorption degree of dauricine increases with perfusion rates; there is no specific absorption site in the whole rat intestinal tract; the absorption of dauricine is very poor and the active transport is involved in the absorption mechanism of dauricine.
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Objective: To investigate the rat intestinal absorption kinetics of danshensu (DS) and protocatechuic aldehyde (PA) in Salviae Miltiorrhizae Radix et Rhizoma extract. Methods: In situ single pass intestinal perfusion model was employed to investigate the effects of perfusion rate, perfusion solution pH value, bile duct ligation, drug concentrations, absorption sites and P-glycoprotein (P-gp) on absorption of DS and PA, and perfusion volume was corrected by gravimetric method. Meanwhile, the concentration of DS and PA in the perfusate were determined by HPLC. Results: The drug absorption constant (Ka) and apparent absorption coefficient (Papp) of DS and PA increased linearly along with the increasing perfusion rates among the ranges of 0.2-0.8 mL/min. pH value of perfusion solution affected drug absorption (P < 0.05), Ka and Papp of DS and PA decreased with increasing pH value at pH values of 7.4, 6.8, and 5.5. And at pH value of 5.5 and 6.8, the absorption had no significant difference, but there was significant difference at pH value between 5.5 and 7.4 (P < 0.05). There was no significant difference in Ka and Papp value between bile duct ligation group and no ligation group. At different absorption sites, K a and Papp of DS in the duodenum, jejunum, ileum, and colon sequence have a downward trend, but not for PA, while PA could be absorbed well at all intestinal segments. In the drug concentrations of 0.8, 1.5, and 2.2 mg/mL, Ka, and Papp of DS decréased with higher concentrations, and PA absorption parameter has non-obvious changes. There was no significant difference in Ka and Papp between the presence of P-gp inhibitor and no P-gp inhibitor. Conclusion: Perfusion rate and pH value have significant influence on absorption of DS and PA. Two water-soluble ingredients could be absorbed at all intestinal segments and DS has better absorption at former intestinal segments. The concentration of the extract has no influence on its absorption parameters of PA, which preliminarily demonstrates that PA is absorbed by passive diffusion mechanism. However, absorption of DS is affected by concentration, indicating that in addition to passive diffusion, it may also have active absorption or facilitation diffusion in absorption process of DS. Moreover, two ingredients are not affected by P-gp efflux.
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0.05).But the P_ eff values were significantly increased in the presence of P-glycoportein(P-gp)inhibitor,verapamil or digoxin.CONCLUSION:Rhamnosylvitexin can be classified into high penetrating drug.Passive diffusion dominates the absorptive transport behavior of rhamnosylvitexin in HLF.There is not a preferential absorption zone in the intestine for rhamnosylvitexin.The absorption and secretion of rhamnosylvitexin in HLF are mediated by the efflux transport system,P-gp.