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K S Pang - One of the best experts on this subject based on the ideXlab platform.
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P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16α-carbonitrile
Drug metabolism and disposition: the biological fate of chemicals, 2006Co-Authors: Shanjun Liu, Debbie Tam, Xianghai Chen, K S PangAbstract:Digoxin, a substrate of P-glycoprotein (Pgp) and cytochrome P450 3a (Cyp3a), was used to illustrate the inductive effects of pregnenolone-16α-carbonitrile (PCN), a ligand of the pregnane X receptor, on the absorption and disposition of [3H]digoxin in the vascularly perfused rat small Intestine Preparation. Although increased Cyp3a protein was observed with Western blotting analysis after PCN treatment, metabolism of digoxin to the digoxigenin bis-digitoxoside metabolite in the rat small Intestine remained insignificant (
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Transactivation of Rat Apical Sodium-Dependent Bile Acid Transporter and Increased Bile Acid Transport by 1α,25-Dihydroxyvitamin D3 via the Vitamin D Receptor
Molecular pharmacology, 2006Co-Authors: Xianghai Chen, Shanjun Liu, Frank Chen, Hartmut Glaeser, Paul A. Dawson, Alan F. Hofmann, Richard B. Kim, Benjamin L. Shneider, K S PangAbstract:Transactivation of the rat apical sodium-dependent bile acid transporter (ASBT; Slc10a2) by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] via the vitamin D receptor (VDR), was studied. Levels of ASBT protein and mRNA were low in the duodenum and high in the ileum, and both were induced by 1,25(OH)2D3. The nuclear receptor protein, VDR, was present uniformly in the duodenum, jejunum, and ileum of the rat small Intestine. The physiological relevance of ASBT induction by 1,25(OH)2D3 was assessed by measuring absorption of cholylsarcosine, a non-metabolized synthetic bile acid analog, from duodenal or ileal closed loops of the perfused rat small Intestine Preparation. Absorption of cholylsarcosine was much greater from the ileal segment (28-fold that of the duodenum under control conditions) and was enhanced with 1,25(OH)2D3 treatment. Transient transfection analysis of the rat ASBT promoter in Caco-2 cells revealed concentration-dependent enhancement of luciferase reporter activity after treatment with 1,25(OH)2D3. The activation by 1,25(OH)2D3 was abrogated after site-directed mutagenesis or deletion of the vitamin D response element (VDRE) in the ASBT promoter. Gel-shift mobility assays of nuclear extracts from rat ileum showed that both rat retinoid X receptor and VDR were bound to the VDRE. The results indicate that rat ASBT gene expression is activated by 1,25(OH)2D3 by specific binding to the VDRE and that such activation enhances ileal bile acid transport. Human ABST mRNA and promoter activity were also increased in Caco-2 cells treated with 1,25(OH)2D3, suggesting a physiological role of VDR in human ileal bile acid homeostasis.
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Absorption of benzoic acid in segmental regions of the vascularly perfused rat small Intestine Preparation.
Drug Metabolism and Disposition, 2001Co-Authors: Diem Cong, Angela K. Y. Fong, K S PangAbstract:Oral bioavailability is a consequence of intestinal absorption, exsorption, and metabolism and is further modulated by the difference in activities among segmental regions. The influence of these factors on the net absorption of benzoic acid (BA), a substrate that is metabolized to hippurate and is transported by the monocarboxylic acid transporter 1, was studied in the recirculating, vascularly perfused, rat small Intestine Preparation. Metabolism of BA was not observed for both systemic and intraluminal injections into segments of varying lengths. But, secretion of BA into lumen was noted. Absorption of BA (0.166–3.68 μmol) introduced at the duodenal end for absorption by the entire Intestine was complete (>95% dose at 2 h) and dose-independent, yielding similar absorption rate constants (ka of 0.0464 min−1). The extent of absorption remained high (92–96% dose) when BA was injected into closed segments of shorter lengths (12 or 20 cm), suggesting a large reserve length of the rat Intestine. However,ka was higher for the jejunum (0.0519 and 0.0564 min−1, respectively, for the 12- and 20-cm segments) and exceeded that for the duodenum (12-cm segment, 0.0442 min−1) and ileum (20-cm segment, 0.0380 min−1) at closed injection sites. The finding paralleled the distribution of monocarboxylic acid transporter isoform 1 detected by Western blotting along the length of the small Intestine. Fits of the systemic and oral data (based on duodenal injection for absorption by the whole Intestine) to the traditional, physiological model and to the segregated flow model (SFM) that describes partial intestinal flow to the enterocyte region showed a better fit with the SFM even though metabolite data were absent.
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route dependent metabolism of morphine in the vascularly perfused rat small Intestine Preparation
Pharmaceutical Research, 2000Co-Authors: M M Doherty, K S PangAbstract:Purpose. 1. To compare the disposition of tracer morphine ([3H]M)following systemic and intraduodenal administration in therecirculating, rat small Intestine Preparation in absence or presence of verapamil(V), an inhibitor of P-glycoprotein. 2. To develop a physiological modelto explain the observations.
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Route-Dependent Metabolism of Morphine in the Vascularly Perfused Rat Small Intestine Preparation
Pharmaceutical Research, 2000Co-Authors: M M Doherty, K S PangAbstract:Purpose . 1. To compare the disposition of tracer morphine ([^3H]M)following systemic and intraduodenal administration in therecirculating, rat small Intestine Preparation in absence or presence of verapamil(V), an inhibitor of P-glycoprotein. 2. To develop a physiological modelto explain the observations. Methods . A bolus dose of [^3H]M was added to the reservoir or injectedinto the duodenum of the rat small Intestine Preparation. V (200 μMin reservoir) was either absent (control studies) or present. Intestinalmicrosomal, incubation studies were performed to evaluate the effectof V on morphine glucuronidation. Results . After systemic administration, [^3H]M was not metabolizedbut was exsorbed into lumen. By contrast, both [^3H]M and the3β-glucuronide metabolite, [^3H]M3G, appeared in reservoir and lumenafter intraduodenal administration. A physiologically-based model thatencompassed absorption, metabolism and secretion was able to describethe route-dependent glucuronidation of M. The presence of V resultedin diminished levels of M3G in perfusate and lumen and mirrored theobservation of decreased glucuronidation in microsomal incubations.Verapamil appeared to be an inhibitor of glucuronidation and notsecretion of M. Conclusions . M was secreted and absorbed by the rat small Intestine.Route-dependent glucuronidation of M was explained by physiologicalmodeling when M was poorly partitioned in intestinal tissue, with alow influx clearance from blood and a even poorer efflux clearancefrom tissue. The poor efflux rendered a much greater metabolism ofM that was initially absorbed from the lumen. V increased the extentof M absorption through inhibition of M glucuronidation.
M M Doherty - One of the best experts on this subject based on the ideXlab platform.
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route dependent metabolism of morphine in the vascularly perfused rat small Intestine Preparation
Pharmaceutical Research, 2000Co-Authors: M M Doherty, K S PangAbstract:Purpose. 1. To compare the disposition of tracer morphine ([3H]M)following systemic and intraduodenal administration in therecirculating, rat small Intestine Preparation in absence or presence of verapamil(V), an inhibitor of P-glycoprotein. 2. To develop a physiological modelto explain the observations.
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Route-Dependent Metabolism of Morphine in the Vascularly Perfused Rat Small Intestine Preparation
Pharmaceutical Research, 2000Co-Authors: M M Doherty, K S PangAbstract:Purpose . 1. To compare the disposition of tracer morphine ([^3H]M)following systemic and intraduodenal administration in therecirculating, rat small Intestine Preparation in absence or presence of verapamil(V), an inhibitor of P-glycoprotein. 2. To develop a physiological modelto explain the observations. Methods . A bolus dose of [^3H]M was added to the reservoir or injectedinto the duodenum of the rat small Intestine Preparation. V (200 μMin reservoir) was either absent (control studies) or present. Intestinalmicrosomal, incubation studies were performed to evaluate the effectof V on morphine glucuronidation. Results . After systemic administration, [^3H]M was not metabolizedbut was exsorbed into lumen. By contrast, both [^3H]M and the3β-glucuronide metabolite, [^3H]M3G, appeared in reservoir and lumenafter intraduodenal administration. A physiologically-based model thatencompassed absorption, metabolism and secretion was able to describethe route-dependent glucuronidation of M. The presence of V resultedin diminished levels of M3G in perfusate and lumen and mirrored theobservation of decreased glucuronidation in microsomal incubations.Verapamil appeared to be an inhibitor of glucuronidation and notsecretion of M. Conclusions . M was secreted and absorbed by the rat small Intestine.Route-dependent glucuronidation of M was explained by physiologicalmodeling when M was poorly partitioned in intestinal tissue, with alow influx clearance from blood and a even poorer efflux clearancefrom tissue. The poor efflux rendered a much greater metabolism ofM that was initially absorbed from the lumen. V increased the extentof M absorption through inhibition of M glucuronidation.
Su Jun Wang - One of the best experts on this subject based on the ideXlab platform.
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The Disposition of Oxymatrine in the Vascularly Perfused Rat Intestine-Liver Preparation and Its Metabolism in Rat Liver Microsomes.
Journal of pharmaceutical sciences, 2016Co-Authors: Li Hua Huang, Yun Ming Zhong, Xiao Hong Xiong, Mei Feng Cen, Xuan Ge Cheng, Gui Xiang Wang, Ji Sheng Chen, Su Jun WangAbstract:The study was aimed to investigate the absorption and metabolism of oxymatrine (OMT) which contributed to its poor bioavailability. Determinations of OMT absorption and metabolism in rats were evaluated using techniques of the in situ perfused rat Intestine-liver Preparation and recirculated Intestine Preparation. Furthermore, chemical inhibition experiments in rat liver microsomes were used to determine the principal cytochrome P450 (CYP) isoforms involved in OMT metabolism. In the Intestine-liver Preparation, the steady state liver extraction ratio (0.753 ± 0.054) of OMT was 33 times higher than that for the Intestine (0.023 ± 0.002). The portal vein mainly consisted of OMT, and was devoid of the metabolite matrine, whereas both OMT and matrine were detected in hepatic vein. With the Intestine Preparation, the extent of OMT absorption at the end of 120 min of perfusion was 4.79 ± 0.352%. The first-order rate constant for OMT absorption was 0.05 ± 0.003 min(-1). The inhibitor of CYP3A2 had strong inhibitory effect on OMT metabolism in a concentration-dependent manner, and value was reduced to 29.73% of control. The 2 perfusion techniques indicated that poor bioavailability of OMT in rats is due mostly to poor absorption and higher hepatic elimination and CYP3A2 appears to contribute to OMT metabolism in rat liver.
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Pharmacokinetics, Pharmacodynamics and Drug Transport and Metabolism The Disposition of Oxymatrine in the Vascularly Perfused Rat Intestine-Liver Preparation and Its Metabolism in Rat Liver Microsomes
2016Co-Authors: Li Hua Huang, Yun Ming Zhong, Xiao Hong Xiong, Mei Feng Cen, Xuan Ge Cheng, Gui Xiang Wang, Ji Sheng Chen, Su Jun WangAbstract:The study was aimed to investigate the absorption and metabolism of oxymatrine (OMT) which contributed to its poor bioavailability. Determinations of OMT absorption and metabolism in rats were evaluated using techniques of the in situ perfused rat Intestine-liver Preparation and recirculated Intestine Preparation. Furthermore, chemical inhibition experiments in rat liver microsomes were used to determine the principal cytochrome P450 (CYP) isoforms involved in OMT metabolism. In the Intestineliver Preparation, the steady state liver extraction ratio (0.753 ± 0.054) of OMT was 33 times higher than that for the Intestine (0.023 ± 0.002). The portal vein mainly consisted of OMT, and was devoid of the metabolite matrine, whereas both OMT and matrine were detected in hepatic vein. With the Intestine Preparation, the extent of OMT absorption at the end of 120 min of perfusion was 4.79 ± 0.352%. The first-order rate constant for OMT absorption was 0.05 ± 0.003 min � 1 . The inhibitor of CYP3A2 had strong inhibitory effect on OMT metabolism in a concentration-dependent manner, and value was reduced to 29.73% of control. The 2 perfusion techniques indicated that poor bioavailability of OMT in rats is due mostly to poor absorption and higher hepatic elimination and CYP3A2 appears to contribute to OMT metabolism in rat liver.
Xianghai Chen - One of the best experts on this subject based on the ideXlab platform.
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P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16α-carbonitrile
Drug metabolism and disposition: the biological fate of chemicals, 2006Co-Authors: Shanjun Liu, Debbie Tam, Xianghai Chen, K S PangAbstract:Digoxin, a substrate of P-glycoprotein (Pgp) and cytochrome P450 3a (Cyp3a), was used to illustrate the inductive effects of pregnenolone-16α-carbonitrile (PCN), a ligand of the pregnane X receptor, on the absorption and disposition of [3H]digoxin in the vascularly perfused rat small Intestine Preparation. Although increased Cyp3a protein was observed with Western blotting analysis after PCN treatment, metabolism of digoxin to the digoxigenin bis-digitoxoside metabolite in the rat small Intestine remained insignificant (
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Transactivation of Rat Apical Sodium-Dependent Bile Acid Transporter and Increased Bile Acid Transport by 1α,25-Dihydroxyvitamin D3 via the Vitamin D Receptor
Molecular pharmacology, 2006Co-Authors: Xianghai Chen, Shanjun Liu, Frank Chen, Hartmut Glaeser, Paul A. Dawson, Alan F. Hofmann, Richard B. Kim, Benjamin L. Shneider, K S PangAbstract:Transactivation of the rat apical sodium-dependent bile acid transporter (ASBT; Slc10a2) by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] via the vitamin D receptor (VDR), was studied. Levels of ASBT protein and mRNA were low in the duodenum and high in the ileum, and both were induced by 1,25(OH)2D3. The nuclear receptor protein, VDR, was present uniformly in the duodenum, jejunum, and ileum of the rat small Intestine. The physiological relevance of ASBT induction by 1,25(OH)2D3 was assessed by measuring absorption of cholylsarcosine, a non-metabolized synthetic bile acid analog, from duodenal or ileal closed loops of the perfused rat small Intestine Preparation. Absorption of cholylsarcosine was much greater from the ileal segment (28-fold that of the duodenum under control conditions) and was enhanced with 1,25(OH)2D3 treatment. Transient transfection analysis of the rat ASBT promoter in Caco-2 cells revealed concentration-dependent enhancement of luciferase reporter activity after treatment with 1,25(OH)2D3. The activation by 1,25(OH)2D3 was abrogated after site-directed mutagenesis or deletion of the vitamin D response element (VDRE) in the ASBT promoter. Gel-shift mobility assays of nuclear extracts from rat ileum showed that both rat retinoid X receptor and VDR were bound to the VDRE. The results indicate that rat ASBT gene expression is activated by 1,25(OH)2D3 by specific binding to the VDRE and that such activation enhances ileal bile acid transport. Human ABST mRNA and promoter activity were also increased in Caco-2 cells treated with 1,25(OH)2D3, suggesting a physiological role of VDR in human ileal bile acid homeostasis.
Jonathan Moss - One of the best experts on this subject based on the ideXlab platform.
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effects of methylnaltrexone on morphine induced inhibition of contraction in isolated guinea pig ileum and human Intestine
European Journal of Pharmacology, 1995Co-Authors: Chun-su Yuan, Joseph F. Foss, Jonathan MossAbstract:Abstract We investigated the effects of methylnaltrexone on morphine-induced inhibition of smooth muscle-strip contraction in isolated guinea-pig ileum and human small Intestine. The longitudinal muscle-strip was immersed in a temperature-controlled (37°C) bath containing a physiological solution of 95% O 2 and 5% CO 2 with pH 7.4. Muscle contraction was elicited by transmural electrical stimulation with a pulse duration of 0.5 ms at frequencies of 1–50 Hz for 5–10 s at 1–3-min intervals. Muscle contraction was blocked by tetrodotoxin or atropine in both Preparations. When methylnaltrexone was applied to the bath, the force produced by muscle contraction was enhanced up to approximately 30%. Stimulation-elicited muscle contraction was inhibited by morphine, which decreased the force of contraction 42 ± 9.5% (S.D.) in the human Intestine Preparation and 35 ± 8.6% in guinea-pig ileum at the inhibitory concentration 70% (IC 70 ). Methylnaltrexone effectively antagonized the effects of morphine-induced inhibition of muscle-strip contraction. In the guinea-pig ileum Preparation, methylnaltrexone at 30, 100 and 300 nM blocked 25 ± 10.5%, 74 ± 7.2% and 89 ± 9.9% of morphine-induced (300 nM) inhibition, respectively. In the human Intestine Preparation, methylnaltrexone at the same concentrations blocked 57 ± 10.9%, 74 ± 12.9% and 92 ± 7.2% of morphine-induced (100 nM) inhibition, respectively. The relative ratio of methylnaltrexone to morphine was higher in human Intestine (1:1) than in the guinea-pig ileum Preparation (1:3). These data provide preliminary information for clinical studies to evaluate the efficacy of methylnaltrexone in preventing or reducing morphine-induced antimotility and antitransit actions.
