Involvement of intestinal efflux and metabolic instability in the pharmacokinetics of platycodin D in rats

Kwon, Mihwa; Ji, Hyeon-Kyeong; Goo, Soo Hyeon; Nam, So Jeong; Kang, Yun Ju; Lee, Eun-Young; Liu, Kwang-Hyeon; Choi, Min‐Koo; Song, Im‐Sook

doi:10.1016/j.dmpk.2017.05.005

Cited by 13 publications

(13 citation statements)

References 12 publications

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“…In addition, the increased culture area and the residence time of microfluidic flow in a convoluted PMI Chip allow the intestinal epithelium to sufficiently interact with the surrounding environment, which can elicit active intercellular responses. The enhanced residence time in a PMI Chip may also be beneficial to perform an accurate transport assay for assessing the absorption or efflux of various drug candidates [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Three-Dimensional Regeneration of Patient-Derived Intestinal Organoid Epithelium in a Physiodynamic Mucosal Interface-on-a-Chip

Shin

Koh

et al. 2020

Micromachines

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The regeneration of the mucosal interface of the human intestine is critical in the host–gut microbiome crosstalk associated with gastrointestinal diseases. The biopsy-derived intestinal organoids provide genetic information of patients with physiological cytodifferentiation. However, the enclosed lumen and static culture condition substantially limit the utility of patient-derived organoids for microbiome-associated disease modeling. Here, we report a patient-specific three-dimensional (3D) physiodynamic mucosal interface-on-a-chip (PMI Chip) that provides a microphysiological intestinal milieu under defined biomechanics. The real-time imaging and computational simulation of the PMI Chip verified the recapitulation of non-linear luminal and microvascular flow that simulates the hydrodynamics in a living human gut. The multiaxial deformations in a convoluted microchannel not only induced dynamic cell strains but also enhanced particle mixing in the lumen microchannel. Under this physiodynamic condition, an organoid-derived epithelium obtained from the patients diagnosed with Crohn’s disease, ulcerative colitis, or colorectal cancer independently formed 3D epithelial layers with disease-specific differentiations. Moreover, co-culture with the human fecal microbiome in an anoxic–oxic interface resulted in the formation of stochastic microcolonies without a loss of epithelial barrier function. We envision that the patient-specific PMI Chip that conveys genetic, epigenetic, and environmental factors of individual patients will potentially demonstrate the pathophysiological dynamics and complex host–microbiome crosstalk to target a patient-specific disease modeling.

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Section: Discussionmentioning

confidence: 99%

Three-Dimensional Regeneration of Patient-Derived Intestinal Organoid Epithelium in a Physiodynamic Mucosal Interface-on-a-Chip

Shin

Koh

et al. 2020

Micromachines

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“…The permeability of metformin with or without RGE treatment was measured according to the method of Kwon et al [31]. Briefly, duodenum, jejunum, and ileum segments were dissected and washed as described earlier.…”

Section: Methodsmentioning

confidence: 99%

“…The effect of RGE on the paracellular permeability was measured using 50 µM Lucifer yellow, a marker compound for paracellular pathway [31] with the same protocol as metformin. A 100 μL aliquot of samples was transferred to 96-well plates and the fluorescence of Lucifer yellow was read directly in a fluorescence plate reader using a 485 nm excitation and an emission filter of 535 nm.…”

Section: Methodsmentioning

confidence: 99%

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Enhanced Intestinal Permeability and Plasma Concentration of Metformin in Rats by the Repeated Administration of Red Ginseng Extract

et al. 2019

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We aimed to assess the potential herb–drug interactions between Korean red ginseng extract (RGE) and metformin in rats in terms of the modulation of metformin transporters, such as organic cation transporter (Oct), multiple toxin and extrusion protein (Mate), and plasma membrane monoamine transporter (Pmat). Single treatment of RGE did not inhibit the in vitro transport activity of OCT1/2 up to 500 µg/mL and inhibited MATE1/2-K with high IC50 value (more than 147.8 µg/mL), suggesting that concomitant used of RGE did not directly inhibit OCT- and MATE-mediated metformin uptake. However, 1-week repeated administration of RGE (1.5 g/kg/day) (1WRA) to rats showed different alterations in mRNA levels of Oct1 depending on the tissue type. RGE increased intestinal Oct1 but decreased hepatic Oct1. However, neither renal Oct1/Oct2 nor Mate1/Pmat expression in duodenum, jejunum, ileum, liver, and kidney were changed in 1WRA rats. RGE repeated dose also increased the intestinal permeability of metformin; however, the permeability of 3-O-methyl-d-glucose and Lucifer yellow was not changed in 1WRA rats, suggesting that the increased permeability of metformin by multiple doses of RGE is substrate-specific. On pharmacokinetic analysis, plasma metformin concentrations following intravenous injection were not changed in 1WRA, consistent with no significant change in renal Oct1, Oct2, and mate1. Repeated doses of RGE for 1 week significantly increased the plasma concentration of metformin, with increased half-life and urinary excretion of metformin following oral administration of metformin (50 mg/kg), which could be attributed to the increased absorption of metformin. In conclusion, repeated administration of RGE showed in vivo pharmacokinetic herb–drug interaction with metformin, with regard to its plasma exposure and increased absorption in rats. These results were consistent with increased intestinal Oct1 and its functional consequence, therefore, the combined therapeutic efficacy needs further evaluation before the combination and repeated administration of RGE and metformin, an Oct1 substrate drug.

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“…Apparent permeability (P app ) of memantine in the presence or absence of cimetidine was determined with slight modification of a method of Kwon et al [ 21 ]. Briefly, the rat jejunum segments mounted on the inserts of the Ussing chambers were acclimatized with Hank’s balanced salt solution (HBSS) for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Drug-Drug Interaction and Responsible Mechanism between Memantine and Cimetidine

2018

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A sensitive and simple chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to evaluate memantine in rat plasma. Memantine and propranolol (internal standard) in rat plasma was extracted using a methanol precipitation method. The standard curve value was 0.2–1000 ng/mL and selectivity, linearity, inter-day and intra-day accuracy and precision were within acceptance criteria. Using this validated method, drug-drug interactions between memantine and cimetidine was measured following co-administration of memantine and cimetidine intravenously and orally. Plasma exposure of memantine was increased by 1.6- and 3.0-fold by co-medication with cimetidine intravenously and orally, respectively. It suggested that the drug interaction occurred during the gut absorption process, which was consistent with the results showing that the intestinal permeability of memantine in the presence of cimetidine was 3.2-fold greater than that of memantine alone. Inhibition of cimetidine on hepatic elimination of memantine rather than renal excretion was also attributed to the drug-drug interaction between memantine and cimetidine, which explained the decreased clearance of memantine by co-medication with cimetidine. In conclusion, the newly developed simple and sensitive LC-MS/MS analytical method was applied to investigate the pharmacokinetic drug-drug interactions of memantine. Plasma exposure of memantine by co-administration with cimetidine was increased because of its enhanced intestinal permeability and the decreased metabolic activity of memantine.

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Involvement of intestinal efflux and metabolic instability in the pharmacokinetics of platycodin D in rats

Cited by 13 publications

References 12 publications

Three-Dimensional Regeneration of Patient-Derived Intestinal Organoid Epithelium in a Physiodynamic Mucosal Interface-on-a-Chip

Three-Dimensional Regeneration of Patient-Derived Intestinal Organoid Epithelium in a Physiodynamic Mucosal Interface-on-a-Chip

Enhanced Intestinal Permeability and Plasma Concentration of Metformin in Rats by the Repeated Administration of Red Ginseng Extract

Pharmacokinetic Drug-Drug Interaction and Responsible Mechanism between Memantine and Cimetidine

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