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Gao Li - One of the best experts on this subject based on the ideXlab platform.
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enhanced Intestinal Absorption of etoposide by self microemulsifying drug delivery systems roles of p glycoprotein and cytochrome p450 3a inhibition
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Gang Zhao, Jiangeng Huang, Luqin Si, Gao LiAbstract:Abstract Etoposide is recognized as a dual P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) substrate drug with poor water-solubility. To improve its solubility and bioavailability, three novel self-microemulsifying drug delivery systems (SMEDDS) contained the known P-gp and CYP3A inhibitory surfactants, Cremophor RH40, Cremophor EL, or Polysorbate 80, were prepared. This work aims to evaluate the enhanced Intestinal Absorption of etoposide SMEDDS as well as to explore the roles of P-gp and CYP3A inhibition in the Absorption process. Etoposide SMEDDS were orally administered to rats for in vivo bioavailability investigation. In situ single-pass Intestinal perfusion with mesenteric vein cannulation was employed to study the drug permeability and Intestinal metabolism. In vitro Caco-2 cell models were applied to study the effects of P-gp and CYP3A inhibition by SMEDDS on the cellular accumulation of etoposide. It was found that the bioavailability and in situ Intestinal Absorption were significantly enhanced by SMEDDS with the order of Polysorbate 80-based SMEDDS > Cremophor EL-based SMEDDS > Cremophor RH40-based SMEDDS. In addition, there was a dramatically high linear correlation between the AUC0–t values and the apparent permeability coefficient values based on the appearance of the drug in mesenteric vein blood. Cellular uptake studies demonstrated that P-gp inhibition by SMEDDS played an important role in etoposide uptake. Moreover, etoposide metabolism was demonstrated to be dramatically inhibited by the three kinds of SMEDDS. These finding may assist in the improvement of the Intestinal Absorption of P-gp and/or CYP3A substrate drugs.
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enhanced Intestinal Absorption of etoposide by self microemulsifying drug delivery systems roles of p glycoprotein and cytochrome p450 3a inhibition
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Gang Zhao, Jiangeng Huang, Luqin Si, Gao LiAbstract:Abstract Etoposide is recognized as a dual P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) substrate drug with poor water-solubility. To improve its solubility and bioavailability, three novel self-microemulsifying drug delivery systems (SMEDDS) contained the known P-gp and CYP3A inhibitory surfactants, Cremophor RH40, Cremophor EL, or Polysorbate 80, were prepared. This work aims to evaluate the enhanced Intestinal Absorption of etoposide SMEDDS as well as to explore the roles of P-gp and CYP3A inhibition in the Absorption process. Etoposide SMEDDS were orally administered to rats for in vivo bioavailability investigation. In situ single-pass Intestinal perfusion with mesenteric vein cannulation was employed to study the drug permeability and Intestinal metabolism. In vitro Caco-2 cell models were applied to study the effects of P-gp and CYP3A inhibition by SMEDDS on the cellular accumulation of etoposide. It was found that the bioavailability and in situ Intestinal Absorption were significantly enhanced by SMEDDS with the order of Polysorbate 80-based SMEDDS > Cremophor EL-based SMEDDS > Cremophor RH40-based SMEDDS. In addition, there was a dramatically high linear correlation between the AUC0–t values and the apparent permeability coefficient values based on the appearance of the drug in mesenteric vein blood. Cellular uptake studies demonstrated that P-gp inhibition by SMEDDS played an important role in etoposide uptake. Moreover, etoposide metabolism was demonstrated to be dramatically inhibited by the three kinds of SMEDDS. These finding may assist in the improvement of the Intestinal Absorption of P-gp and/or CYP3A substrate drugs.
Akira Yamamoto - One of the best experts on this subject based on the ideXlab platform.
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Absorption enhancing effects of gemini surfactant on the Intestinal Absorption of poorly absorbed hydrophilic drugs including peptide and protein drugs in rats
International Journal of Pharmaceutics, 2016Co-Authors: Tammam Alama, Kosuke Kusamori, Hidemasa Katsumi, Toshiyasu Sakane, Akira YamamotoAbstract:In general, the Intestinal Absorption of small hydrophilic molecules and macromolecules like peptides, after oral administration is very poor. Absorption enhancers are considered to be one of the most promising agents to enhance the Intestinal Absorption of drugs. In this research, we focused on a gemini surfactant, a new type of Absorption enhancer. The Intestinal Absorption of drugs, with or without sodium dilauramidoglutamide lysine (SLG-30), a gemini surfactant, was examined by an in situ closed-loop method in rats. The Intestinal Absorption of 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-dextrans (FDs) was significantly enhanced in the presence of SLG-30, such effect being reversible. Furthermore, the calcium levels in the plasma significantly decreased when calcitonin was co-administered with SLG-30, suggestive of the increased Intestinal Absorption of calcitonin. In addition, no significant increase in the of lactate dehydrogenase (LDH) activity or in protein release from the Intestinal epithelium was observed in the presence of SLG-30, suggestive of the safety of this compound. These findings indicate that SLG-30 is an effective Absorption-enhancer for improving the Intestinal Absorption of poorly absorbed drugs, without causing serious damage to the Intestinal epithelium.
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polyamidoamine dendrimers as novel potential Absorption enhancers for improving the small Intestinal Absorption of poorly absorbable drugs in rats
Journal of Controlled Release, 2011Co-Authors: Yulian Lin, Hidemasa Katsumi, Toshiyasu Sakane, Takeo Fujimori, Naoko Kawaguchi, Yuiko Tsujimoto, Mariko Nishimi, Zhengqi Dong, Akira YamamotoAbstract:Effects of polyamidoamine (PAMAM) dendrimers on the Intestinal Absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF), fluorescein isothiocyanate-dextrans (FDs) with various molecular weights, calcitonin and insulin were used as model drugs of poorly absorbable drugs. The Absorption of CF, FD4 and calcitonin from the rat small intestine was significantly enhanced in the presence of PAMAM dendrimers. The Absorption-enhancing effects of PAMAM dendrimers for improving the small Intestinal Absorption of CF were concentration and generation dependent and a maximal Absorption-enhancing effect was observed in the presence of 0.5% (w/v) G2 PAMAM dendrimer. However, G2 PAMAM dendrimer had almost no Absorption-enhancing effect on the small Intestinal Absorption of macromolecular drugs including FD10 and insulin. Overall, the Absorption-enhancing effects of G2 PAMAM dendrimer in the small intestine decreased as the molecular weights of drug increased. However, G2 PAMAM dendrimer did not enhance the Intestinal Absorption of these drugs with different molecular weights in the large intestine. Furthermore, we evaluated the Intestinal membrane damage with or without G2 PAMAM dendrimer. G2 PAMAM dendrimer (0.5% (w/v)) significantly increased the activities of lactate dehydrogenase (LDH) and the amounts of protein released from the Intestinal membranes, but the activities and amounts of these toxic markers were less than those in the presence of 3% Triton X-100 used as a positive control. Moreover, G2 PAMAM dendrimer at concentrations of 0.05% (w/v) and 0.1% (w/v) did not increase the activities and amounts of these toxic markers. These findings suggested that PAMAM dendrimers at lower concentrations might be potential and safe Absorption enhancers for improving Absorption of poorly absorbable drugs from the small intestine.
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development of oligoarginine drug conjugates linked to new peptidic self cleavable spacers toward effective Intestinal Absorption
Bioorganic & Medicinal Chemistry Letters, 2007Co-Authors: Yoshio Hayashi, Takuya Fujita, Akira Yamamoto, Kentaro Takayama, Yuka Suehisa, Jeffreytri Nguyen, Shiroh Futaki, Yoshiaki KisoAbstract:Abstract We designed and synthesized new peptidic self-cleavable spacers that released a parent drug via succinimide formation and the oligoarginine-based cargo-transporter (OACT) system. The self-cleavable efficacy of these compounds was studied and the conversion time was controlled by an amino acid side-chain structure next to the succinyl moiety on the spacer. These novel self-cleavable spacers are promising for developments of the OACT system as means to potentially enhance Intestinal Absorption of parent drugs.
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what kinds of substrates show p glycoprotein dependent Intestinal Absorption comparison of verapamil with vinblastine
Drug Metabolism and Pharmacokinetics, 2006Co-Authors: Takuo Ogihara, Takuya Fujita, Akira Yamamoto, Masatsugu Kamiya, Makoto Ozawa, Shinji Yamashita, Shuhei Ohnishi, Yasuo IsomuraAbstract:The influence of P-glycoprotein (P-gp) on Intestinal Absorption of drugs was investigated by comparison of the uptakes of two P-gp substrates, verapamil and vinblastine, using Intestinal segments of wild-type and mdr1a/1b gene-deficient (mdr1a/1b(-/-)) mice, and Caco-2 cells. When [(3)H]vinblastine was injected into Intestinal segments of wild-type mice, vinblastine was absorbed from duodenum and ileum, but not from jejunum. This difference among Intestinal regions could not be explained by segmental differences of mdr1a mRNA expression. In Caco-2 cells, it was found that vinblastine had a high value of efflux/influx ratio (an index of affinity for P-gp) of 12.1, and a low permeability of less than 1 x 10(-6) cm/sec. The corresponding values for verapamil were 4.9 and 10.6 x 10(-6) cm/sec, respectively. After oral administration of [(3)H]vinblastine to mice, the maximum concentration (C(max)) and the area under the plasma concentration time-curve from time 0 to 24 hr (AUC(0-24 hr)) for mdr1a/1b(-/-) mice were 1.5 times greater than those for wild-type mice, while these parameters were not significantly different between the two strains in the case of [(3)H]verapamil. Therefore, P-gp substrates may be classified into at least two types, i.e., verapamil-type, for which the Intestinal Absorption is unaffected by P-gp, and vinblastine-type, for which the Intestinal Absorption is influenced by P-gp. Vinblastine-type P-gp substrates, with low permeability and high affinity for P-gp, would be unfavorable candidates for oral drugs.
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effects of various protease inhibitors on the Intestinal Absorption and degradation of insulin in rats
Pharmaceutical Research, 1994Co-Authors: Akira Yamamoto, Masahiro Murakami, Takuya Fujita, Toshio Taniguchi, Kaori Rikyuu, Tomoko Tsuji, Shozo MuranishiAbstract:The effects of protease inhibitors on the Intestinal Absorption of insulin were investigated in situ in closed small and large Intestinal loops in rats, and the stability of insulin was examined in homogenates of the small and large intestine. The Intestinal Absorption of insulin was evaluated by its hypoglycemic effect. When insulin alone was administered into small or large Intestinal loops, no marked hypoglycemic response was observed in either region. Of the coadministered protease inhibitors, soybean trypsin inhibitor (1.5, 10 mg/ml) marginally promoted insulin Absorption from the large intestine, whereas aprotinin (10 mg/ml) did to a moderate degree. However, a significant hypoglycemic effect was obtained following large Intestinal administration of insulin with 20 mM of Na-glycocholate, camostat mesilate and bacitracin, when compared with the controls. In contrast, we found little hypoglycemic effect following small Intestinal coadministration of insulin with these protease inhibitors. In the stability experiment, bacitracin, camostat mesilate and Na-glycocholate were effective in reducing insulin degradation in both small and large Intestinal homogenates. It was found that the reduction in the proteolytic rate of insulin was related to the decrease in plasma glucose concentration by these protease inhibitors in the large intestine. These findings suggest that coadministration of protease inhibitors would be useful for improving the large Intestinal Absorption of insulin.
Ian Larson - One of the best experts on this subject based on the ideXlab platform.
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chitosan nanoparticles enhance the Intestinal Absorption of the green tea catechins catechin and epigallocatechin gallate
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Admire Dube, Joseph A Nicolazzo, Ian LarsonAbstract:Catechins found in green tea have received considerable attention due to their favourable biological properties which include cardioprotective, neuroprotective and anti-cancer effects. However, their therapeutic potential is limited by their low oral bioavailability, attributed to poor stability and Intestinal Absorption. We encapsulated (+)-catechin (C) and (-)-epigallocatechin gallate (EGCg) in chitosan nanoparticles (CS NP) as a means of enhancing their Intestinal Absorption. Using excised mouse jejunum in Ussing chambers, encapsulation significantly enhanced (p<0.05) Intestinal Absorption. The cumulative amounts transported after encapsulation were significantly higher (p<0.05), i.e. 302.1+/-46.1 vs 206.8+/-12.6ng/cm(2) and 102.7+/-12.4 vs 57.9+/-7.9ng/cm(2) for C and EGCg, respectively. The mechanism by which Absorption was enhanced was not through an effect of CS NPs on Intestinal paracellular or passive transcellular transport processes (as shown by transport of (14)C-mannitol and (3)H-propranolol) or an effect on efflux proteins (as shown by transport of (3)H-digoxin) but was likely due to stabilization of catechins after encapsulation (99.7+/-0.7 vs 94.9+/-3.8% and 56.9+/-3.0 vs 1.3+/-1.7% of the initial C and EGCg concentration remaining, respectively). This study demonstrates that encapsulation of catechins in CS NPs enhances their Intestinal Absorption and is a promising strategy for improving their bioavailability.
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chitosan nanoparticles enhance the Intestinal Absorption of the green tea catechins catechin and epigallocatechin gallate
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Admire Dube, Joseph A Nicolazzo, Ian LarsonAbstract:Abstract Catechins found in green tea have received considerable attention due to their favourable biological properties which include cardioprotective, neuroprotective and anti-cancer effects. However, their therapeutic potential is limited by their low oral bioavailability, attributed to poor stability and Intestinal Absorption. We encapsulated (+)-catechin (C) and (−)-epigallocatechin gallate (EGCg) in chitosan nanoparticles (CS NP) as a means of enhancing their Intestinal Absorption. Using excised mouse jejunum in Ussing chambers, encapsulation significantly enhanced ( p p vs 206.8 ± 12.6 ng/cm 2 and 102.7 ± 12.4 vs 57.9 ± 7.9 ng/cm 2 for C and EGCg, respectively. The mechanism by which Absorption was enhanced was not through an effect of CS NPs on Intestinal paracellular or passive transcellular transport processes (as shown by transport of 14 C-mannitol and 3 H-propranolol) or an effect on efflux proteins (as shown by transport of 3 H-digoxin) but was likely due to stabilization of catechins after encapsulation (99.7 ± 0.7 vs 94.9 ± 3.8% and 56.9 ± 3.0 vs 1.3 ± 1.7% of the initial C and EGCg concentration remaining, respectively). This study demonstrates that encapsulation of catechins in CS NPs enhances their Intestinal Absorption and is a promising strategy for improving their bioavailability.
Gang Zhao - One of the best experts on this subject based on the ideXlab platform.
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enhanced Intestinal Absorption of etoposide by self microemulsifying drug delivery systems roles of p glycoprotein and cytochrome p450 3a inhibition
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Gang Zhao, Jiangeng Huang, Luqin Si, Gao LiAbstract:Abstract Etoposide is recognized as a dual P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) substrate drug with poor water-solubility. To improve its solubility and bioavailability, three novel self-microemulsifying drug delivery systems (SMEDDS) contained the known P-gp and CYP3A inhibitory surfactants, Cremophor RH40, Cremophor EL, or Polysorbate 80, were prepared. This work aims to evaluate the enhanced Intestinal Absorption of etoposide SMEDDS as well as to explore the roles of P-gp and CYP3A inhibition in the Absorption process. Etoposide SMEDDS were orally administered to rats for in vivo bioavailability investigation. In situ single-pass Intestinal perfusion with mesenteric vein cannulation was employed to study the drug permeability and Intestinal metabolism. In vitro Caco-2 cell models were applied to study the effects of P-gp and CYP3A inhibition by SMEDDS on the cellular accumulation of etoposide. It was found that the bioavailability and in situ Intestinal Absorption were significantly enhanced by SMEDDS with the order of Polysorbate 80-based SMEDDS > Cremophor EL-based SMEDDS > Cremophor RH40-based SMEDDS. In addition, there was a dramatically high linear correlation between the AUC0–t values and the apparent permeability coefficient values based on the appearance of the drug in mesenteric vein blood. Cellular uptake studies demonstrated that P-gp inhibition by SMEDDS played an important role in etoposide uptake. Moreover, etoposide metabolism was demonstrated to be dramatically inhibited by the three kinds of SMEDDS. These finding may assist in the improvement of the Intestinal Absorption of P-gp and/or CYP3A substrate drugs.
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enhanced Intestinal Absorption of etoposide by self microemulsifying drug delivery systems roles of p glycoprotein and cytochrome p450 3a inhibition
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Gang Zhao, Jiangeng Huang, Luqin Si, Gao LiAbstract:Abstract Etoposide is recognized as a dual P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) substrate drug with poor water-solubility. To improve its solubility and bioavailability, three novel self-microemulsifying drug delivery systems (SMEDDS) contained the known P-gp and CYP3A inhibitory surfactants, Cremophor RH40, Cremophor EL, or Polysorbate 80, were prepared. This work aims to evaluate the enhanced Intestinal Absorption of etoposide SMEDDS as well as to explore the roles of P-gp and CYP3A inhibition in the Absorption process. Etoposide SMEDDS were orally administered to rats for in vivo bioavailability investigation. In situ single-pass Intestinal perfusion with mesenteric vein cannulation was employed to study the drug permeability and Intestinal metabolism. In vitro Caco-2 cell models were applied to study the effects of P-gp and CYP3A inhibition by SMEDDS on the cellular accumulation of etoposide. It was found that the bioavailability and in situ Intestinal Absorption were significantly enhanced by SMEDDS with the order of Polysorbate 80-based SMEDDS > Cremophor EL-based SMEDDS > Cremophor RH40-based SMEDDS. In addition, there was a dramatically high linear correlation between the AUC0–t values and the apparent permeability coefficient values based on the appearance of the drug in mesenteric vein blood. Cellular uptake studies demonstrated that P-gp inhibition by SMEDDS played an important role in etoposide uptake. Moreover, etoposide metabolism was demonstrated to be dramatically inhibited by the three kinds of SMEDDS. These finding may assist in the improvement of the Intestinal Absorption of P-gp and/or CYP3A substrate drugs.
Admire Dube - One of the best experts on this subject based on the ideXlab platform.
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chitosan nanoparticles enhance the Intestinal Absorption of the green tea catechins catechin and epigallocatechin gallate
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Admire Dube, Joseph A Nicolazzo, Ian LarsonAbstract:Catechins found in green tea have received considerable attention due to their favourable biological properties which include cardioprotective, neuroprotective and anti-cancer effects. However, their therapeutic potential is limited by their low oral bioavailability, attributed to poor stability and Intestinal Absorption. We encapsulated (+)-catechin (C) and (-)-epigallocatechin gallate (EGCg) in chitosan nanoparticles (CS NP) as a means of enhancing their Intestinal Absorption. Using excised mouse jejunum in Ussing chambers, encapsulation significantly enhanced (p<0.05) Intestinal Absorption. The cumulative amounts transported after encapsulation were significantly higher (p<0.05), i.e. 302.1+/-46.1 vs 206.8+/-12.6ng/cm(2) and 102.7+/-12.4 vs 57.9+/-7.9ng/cm(2) for C and EGCg, respectively. The mechanism by which Absorption was enhanced was not through an effect of CS NPs on Intestinal paracellular or passive transcellular transport processes (as shown by transport of (14)C-mannitol and (3)H-propranolol) or an effect on efflux proteins (as shown by transport of (3)H-digoxin) but was likely due to stabilization of catechins after encapsulation (99.7+/-0.7 vs 94.9+/-3.8% and 56.9+/-3.0 vs 1.3+/-1.7% of the initial C and EGCg concentration remaining, respectively). This study demonstrates that encapsulation of catechins in CS NPs enhances their Intestinal Absorption and is a promising strategy for improving their bioavailability.
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chitosan nanoparticles enhance the Intestinal Absorption of the green tea catechins catechin and epigallocatechin gallate
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Admire Dube, Joseph A Nicolazzo, Ian LarsonAbstract:Abstract Catechins found in green tea have received considerable attention due to their favourable biological properties which include cardioprotective, neuroprotective and anti-cancer effects. However, their therapeutic potential is limited by their low oral bioavailability, attributed to poor stability and Intestinal Absorption. We encapsulated (+)-catechin (C) and (−)-epigallocatechin gallate (EGCg) in chitosan nanoparticles (CS NP) as a means of enhancing their Intestinal Absorption. Using excised mouse jejunum in Ussing chambers, encapsulation significantly enhanced ( p p vs 206.8 ± 12.6 ng/cm 2 and 102.7 ± 12.4 vs 57.9 ± 7.9 ng/cm 2 for C and EGCg, respectively. The mechanism by which Absorption was enhanced was not through an effect of CS NPs on Intestinal paracellular or passive transcellular transport processes (as shown by transport of 14 C-mannitol and 3 H-propranolol) or an effect on efflux proteins (as shown by transport of 3 H-digoxin) but was likely due to stabilization of catechins after encapsulation (99.7 ± 0.7 vs 94.9 ± 3.8% and 56.9 ± 3.0 vs 1.3 ± 1.7% of the initial C and EGCg concentration remaining, respectively). This study demonstrates that encapsulation of catechins in CS NPs enhances their Intestinal Absorption and is a promising strategy for improving their bioavailability.
