scholarly journals In-Depth Characterization of EpiIntestinal Microtissue as a Model for Intestinal Drug Absorption and Metabolism in Human

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 405 ◽  
Author(s):  
Yunhai Cui ◽  
Stephanie Claus ◽  
David Schnell ◽  
Frank Runge ◽  
Caroline MacLean
Keyword(s):  
Drug Absorption ◽  
Oral Absorption ◽  
Human Intestine ◽  
Cancer Resistance ◽  
Holistic Model ◽  
Glycoprotein P ◽  
Intestinal Drug Absorption ◽  
Fraction Absorbed ◽  
Vitro Model

The Caco-2 model is a well-accepted in vitro model for the estimation of fraction absorbed in human intestine. Due to the lack of cytochrome P450 3A4 (CYP3A4) activities, Caco-2 model is not suitable for the investigation of intestinal first-pass metabolism. The purpose of this study is to evaluate a new human intestine model, EpiIntestinal microtissues, as a tool for the prediction of oral absorption and metabolism of drugs in human intestine. The activities of relevant drug transporters and drug metabolizing enzymes, including MDR1 P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), CYP3A4, CYP2J2, UDP-glucuronosyltransferases (UGT), carboxylesterases (CES), etc., were detected in functional assays with selective substrates and inhibitors. Compared to Caco-2, EpiIntestinal microtissues proved to be a more holistic model for the investigation of drug absorption and metabolism in human gastrointestinal tract.

Expression, regulation and function of intestinal drug transporters: an update

2017 ◽  
Vol 398 (2) ◽  
pp. 175-192 ◽  
Author(s):  
Janett Müller ◽  
Markus Keiser ◽  
Marek Drozdzik ◽  
Stefan Oswald
Keyword(s):  
Drug Absorption ◽  
Drug Transport ◽  
Drug Exposure ◽  
Oral Absorption ◽  
Basolateral Membrane ◽  
Oral Drug ◽  
Human Intestine ◽  
Intestinal Drug Absorption ◽  
Intestinal Transporters ◽  
And Function

Abstract Although oral drug administration is currently the favorable route of administration, intestinal drug absorption is challenged by several highly variable and poorly predictable processes such as gastrointestinal motility, intestinal drug solubility and intestinal metabolism. One further determinant identified and characterized during the last two decades is the intestinal drug transport that is mediated by several transmembrane proteins such as P-gp, BCRP, PEPT1 and OATP2B1. It is well-established that intestinal transporters can affect oral absorption of many drugs in a significant manner either by facilitating their cellular uptake or by pumping them back to gut lumen, which limits their oral bioavailability. Their functional relevance becomes even more apparent in cases of unwanted drug-drug interactions when concomitantly given drugs that cause transporter induction or inhibition, which in turn leads to increased or decreased drug exposure. The longitudinal expression of several intestinal transporters is not homogeneous along the human intestine, which may have functional implications on the preferable site of intestinal drug absorption. Besides the knowledge about the expression of pharmacologically relevant transporters in human intestinal tissue, their exact localization on the apical or basolateral membrane of enterocytes is also of interest but in several cases debatable. Finally, there is obviously a coordinative interplay of intestinal transporters (apical–basolateral), intestinal enzymes and transporters as well as intestinal and hepatic transporters. This review aims to give an updated overview about the expression, localization, regulation and function of clinically relevant transporter proteins in the human intestine.

scholarly journals Characterization of P-Glycoprotein Inhibitors for Evaluating the Effect of P-Glycoprotein on the Intestinal Absorption of Drugs

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 388
Author(s):  
Yusuke Kono ◽  
Iichiro Kawahara ◽  
Kohei Shinozaki ◽  
Ikuo Nomura ◽  
Honoka Marutani ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Drug Absorption ◽  
Absorption Rate ◽  
Oral Absorption ◽  
Cancer Resistance ◽  
Wild Type ◽  
Glycoprotein P ◽  
Cell Monolayers ◽  
P Glycoprotein ◽  
New Chemical Entities

For developing oral drugs, it is necessary to predict the oral absorption of new chemical entities accurately. However, it is difficult because of the involvement of efflux transporters, including P-glycoprotein (P-gp), in their absorption process. In this study, we conducted a comparative analysis on the inhibitory activities of seven P-gp inhibitors (cyclosporin A, GF120918, LY335979, XR9576, WK-X-34, VX-710, and OC144-093) to evaluate the effect of P-gp on drug absorption. GF120918, LY335979, and XR9576 significantly decreased the basal-to-apical transport of paclitaxel, a P-gp substrate, across Caco-2 cell monolayers. GF120918 also inhibited the basal-to-apical transport of mitoxantrone, a breast cancer resistance protein (BCRP) substrate, in Caco-2 cells, whereas LY335979 hardly affected the mitoxantrone transport. In addition, the absorption rate of paclitaxel after oral administration in wild-type mice was significantly increased by pretreatment with LY335979, and it was similar to that in mdr1a/1b knockout mice. Moreover, the absorption rate of topotecan, a BCRP substrate, in wild-type mice pretreated with LY335979 was similar to that in mdr1a/1b knockout mice but significantly lower than that in bcrp knockout mice. These results indicate that LY335979 has a selective inhibitory activity for P-gp, and would be useful for evaluating the contribution of P-gp to drug absorption.

scholarly journals P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β

2009 ◽  
Vol 29 (6) ◽  
pp. 1079-1083 ◽  
Author(s):  
Leon M Tai ◽  
A Jane Loughlin ◽  
David K Male ◽  
Ignacio A Romero
Keyword(s):  
Breast Cancer ◽  
Human Brain ◽  
Breast Cancer Resistance Protein ◽  
Amyloid Β ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
The Brain

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.

PAMPA—A drug absorption in vitro model

2006 ◽  
Vol 28 (1-2) ◽  
pp. 43-50 ◽  
Author(s):  
Alex Avdeef ◽  
Oksana Tsinman
Keyword(s):  
Drug Absorption ◽  
In Vitro Model ◽  
Vitro Model

PAMPA—a drug absorption in vitro model

2003 ◽  
Vol 20 (4-5) ◽  
pp. 393-402 ◽  
Author(s):  
Jeffrey A Ruell ◽  
Konstantin L Tsinman ◽  
Alex Avdeef
Keyword(s):  
Drug Absorption ◽  
In Vitro Model ◽  
Vitro Model

A physiologically based biopharmaceutical analysis of zolpidem

2021 ◽  
Author(s):  
◽  
Rafael Leal Monteiro Paraiso
Keyword(s):  
Drug Development ◽  
Drug Absorption ◽  
Oral Absorption ◽  
Food Effect ◽  
Simulation Software ◽  
Oral Drug ◽  
Oral Drug Absorption ◽  
Physiologically Based

Computational oral absorption models, in particular PBBM models, provide a powerful tool for researchers and pharmaceutical scientists in drug discovery and formulation development, as they mimic and can describe the physiologically processes relevant to the oral absorption. PBBM models provide in vivo context to in vitro data experiments and allow for a dynamic understanding of in vivo drug disposition that is not typically provided by data from standard in vitro assays. Investigations using these models permit informed decision-making, especially regarding to formulation strategies in drug development. PBBM models, but can also be used to investigate and provide insight into mechanisms responsible for complex phenomena such as food effect in drug absorption. Although there are obviously still some gaps regarding the in silico construction of the gastrointestinal environment, ongoing research in the area of oral drug absorption (e.g. the UNGAP, AGE-POP and InPharma projects) will increase knowledge and enable improvement of these models. PBBM can nowadays provide an alternative approach to the development of in vitro–in vivo correlations. The case studies presented in this thesis demonstrate how PBBM can address a mechanistic understanding of the negative food effect and be used to set clinically relevant dissolution specification for zolpidem immediate release tablets. In both cases, we demonstrated the importance of integrating drug properties with physiological variables to mechanistically understand and observe the impact of these parameters on oral drug absorption. Various complex physiological processes are initiated upon food consumption, which can enhance or reduce a drug’s dissolution, solubility, and permeability and thus lead to changes in drug absorption. With improvements in modeling and simulation software and design of in vitro studies, PBBM modeling of food effects may eventually serve as a surrogate for clinical food effect studies for new doses and formulations or drugs. Furthermore, the application of these models may be even more critical in case of compounds where execution of clinical studies in healthy volunteers would be difficult (e.g., oncology drugs). In the fourth chapter we have demonstrated the establishment of the link between biopredictive in vitro dissolution testing (QC or biorelevant method) PBBM coupled with PD modeling opens the opportunity to set truly clinically relevant specifications for drug release. This approach can be extended to other drugs regardless of its classification according to the BCS. With the increased adoption of PBBM, we expect that best practices in development and verification of these models will be established that can eventually inform a regulatory guidance. Therefore, the application of Physiologically Based Biopharmaceutical Modelling is an area with great potential to streamline late-stage drug development and impact on regulatory approval procedures. Freie Schlagwörter / Tags

scholarly journals LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats

Pharmaceutics ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 135 ◽  
Author(s):  
Seung Han ◽  
Qili Lu ◽  
Kyeong Lee ◽  
Young Choi
Keyword(s):  
Oral Bioavailability ◽  
Oral Absorption ◽  
Ussing Chamber ◽  
Absolute Bioavailability ◽  
Time Curve ◽  
Glycoprotein P ◽  
Dose Concentration ◽  
Chamber Studies

P-glycoprotein (P-gp)-mediated efflux of docetaxel in the gastrointestinal tract mainly impedes its oral chemotherapy. Recently, LC478, a novel di-substituted adamantyl derivative, was identified as a non-cytotoxic P-gp inhibitor in vitro. Here, we assessed whether LC478 enhances the oral bioavailability of docetaxel in vitro and in vivo. LC478 inhibited P-gp mediated efflux of docetaxel in Caco-2 cells. In addition, 100 mg/kg of LC478 increased intestinal absorption of docetaxel, which led to an increase in area under plasma concentration-time curve (AUC) and absolute bioavailability of docetaxel in rats. According to U.S. FDA criteria (I, an inhibitor concentration in vivo tissue)/(IC50, inhibitory constant in vitro) >10 determines P-gp inhibition between in vitro and in vivo. The values 15.6–20.5, from (LC478 concentration in intestine, 9.37–12.3 μM)/(IC50 of LC478 on P-gp inhibition in Caco-2 cell, 0.601 μM) suggested that 100 mg/kg of LC478 sufficiently inhibited P-gp to enhance oral absorption of docetaxel. Moreover, LC478 inhibited P-gp mediated efflux of docetaxel in the ussing chamber studies using rat small intestines. Our study demonstrated that the feasibility of LC478 as an ideal enhancer of docetaxel bioavailability by P-gp inhibition in dose (concentration)-dependent manners.

scholarly journals Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

2018 ◽  
Vol 45 (2) ◽  
pp. 591-604 ◽  
Author(s):  
Guinever Eustaquio do Imperio ◽  
Enrrico Bloise ◽  
Mohsen Javam ◽  
Phetcharawan Lye ◽  
Andrea Constantinof ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Staining Intensity ◽  
Distinct Pattern ◽  
Mrna Levels ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Immunological Responses

Background/Aims: The ATP-binding cassette (ABC) transporters mediate drug biodisposition and immunological responses in the placental barrier. In vitro infective challenges alter expression of specific placental ABC transporters. We hypothesized that chorioamnionitis induces a distinct pattern of ABC transporter expression. Methods: Gene expression of 50 ABC transporters was assessed using TaqMan® Human ABC Transporter Array, in preterm human placentas without (PTD; n=6) or with histological chorioamnionitis (PTDC; n=6). Validation was performed using qPCR, immunohistochemistry and Western blot. MicroRNAs known to regulate P-glycoprotein (P-gp) were examined by qPCR. Results: Up-regulation of ABCB9, ABCC2 and ABCF2 mRNA was detected in chorioamnionitis (p<0.05), whereas placental ABCB1 (P-gp; p=0.051) and ABCG2 (breast cancer resistance protein-BCRP) mRNA levels (p=0.055) approached near significant up-regulation. In most cases, the magnitude of the effect significantly correlated to the severity of inflammation. Upon validation, increased placental ABCB1 and ABCG2 mRNA levels (p<0.05) were observed. At the level of immunohistochemistry, while BCRP was increased (p<0.05), P-gp staining intensity was significantly decreased (p<0.05) in PTDC. miR-331-5p, involved in P-gp suppression, was upregulated in PTDC (p<0.01) and correlated to the grade of chorioamnionitis (p<0.01). Conclusions: Alterations in the expression of ABC transporters will likely lead to modified transport of clinically relevant compounds at the inflamed placenta. A better understanding of the potential role of these transporters in the events surrounding PTD may also enable new strategies to be developed for prevention and treatment of PTD.

Addition of Optimized Bovine Serum Albumin Level in a High-Throughput Caco-2 Assay Enabled Accurate Permeability Assessment for Lipophilic Compounds

2019 ◽  
Vol 24 (7) ◽  
pp. 738-744
Author(s):  
Xianmei Cai ◽  
Shilpa Madari ◽  
Aaron Walker ◽  
Anthony Paiva ◽  
Ying Li ◽  
...  
Keyword(s):  
Bovine Serum Albumin ◽  
Serum Albumin ◽  
Bovine Serum ◽  
Oral Absorption ◽  
Albumin Level ◽  
Systematic Evaluation ◽  
Lipophilic Compounds ◽  
Reliable Assessment ◽  
Vitro Model

The Caco-2 permeability assay is a well-accepted in vitro model to evaluate compounds’ potential for oral absorption at early discovery. However, for many lipophilic compounds, no meaningful Caco-2 data could be generated due to their low solubility in assay buffer and/or poor recovery from the assay. In our previous study, we reported an organic catch approach to improve compound recovery. To further reduce compound loss and increase solubility in aqueous buffer, we explored the addition of bovine serum albumin (BSA). However, in contrast to the commonly used BSA level at 4%, a lower level of BSA was selected in an effort to minimize the potential risk of missing the identification of efflux substrates, and to avoid the extensive sample cleanup needed for 4% BSA. Through a systematic evaluation, it was found that 0.5% BSA was effective in enhancing compound solubility and reducing nonspecific binding, which allowed reliable assessment of the permeability and efflux potential for lipophilic compounds. Also, with an optimized sample handling process, no extra sample cleanup was required before liquid chromatography–mass spectrometry (LC-MS) analysis. The implementation of this assay has enabled accurate permeability assessment for compounds that had poor solubility and/or poor mass balance under the non-BSA assay conditions.

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