scholarly journals Oral paclitaxel with encequidar compared to intravenous paclitaxel in patients with advanced cancer: a randomised crossover pharmacokinetic study.

2021 ◽  
Author(s):  
Christopher Jackson ◽  
C Hung ◽  
Eva Segelov ◽  
Paula Barlow ◽  
Hans Prenen ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Experimental Approach ◽  
Geometric Mean ◽  
Absolute Bioavailability ◽  
Geometric Mean Ratio ◽  
Glycoprotein P ◽  
Acceptable Range ◽  
P Glycoprotein ◽  
Repeat Administration ◽  
Oral Paclitaxel

Background and purpose: Paclitaxel is a widely used anti-neoplastic agent but has low oral bioavailability due to gut extrusion by P-glycoprotein (P-gp). Oral paclitaxel could be more convenient, less resource intensive, and more tolerable than intravenous administration. Encequidar (HM30181A) is a novel, minimally absorbed gut specific P-gp inhibitor. We tested whether administration of oral paclitaxel with encequidar (oPac+E) achieved comparable AUC to intravenous paclitaxel (IVP) 80mg/m2. Experimental approach: We conducted a multi-centre randomised crossover study with two treatment periods. Patients (pts) with advanced cancer received either oral paclitaxel 615mg/m2 divided over three days and encequidar 15mg orally one-hour prior, followed by IVP 80mg/m2, or the reverse sequence. PK blood samples were taken up to day 9 for oPac+E and day 5 for IVP. Key Results: 42 pts were enrolled; 35 completed both treatment periods. AUC0-∞was 5033.5 +/- 1401.1 ng.h/mL for oPac+E and 5595.9 +/- 1264.1 ng.h/mL with IVP. The geometric mean ratio (GMR) for AUC was 89.5% (90% CI 83.9-95.5). Mean absolute bioavailability of oPac+E was 12%. PK parameters did not change meaningfully after 4 weeks administration of oPac+E in an extension study. G3 treatment emergent adverse events occurred in 7 (18%) pts with oPac+E and 2 (5%) with IVP. 75% of pts preferred oPac+E over IVP. Conclusion and Implications: GMR for AUC was within the predefined acceptable range of 80%-125% for demonstrating equivalence. oPac+E is tolerable and there is no evidence of P-gp induction with repeat administration. With further study, oPac+E is a candidate to replace IVP.

scholarly journals Interaction between Fexofenadine and CYP Phenotyping Probe Drugs in Geneva Cocktail

2019 ◽  
Vol 9 (4) ◽  
pp. 45 ◽  
Author(s):  
Marija Bosilkovska ◽  
Gaelle Magliocco ◽  
Jules Desmeules ◽  
Caroline Samer ◽  
Youssef Daali
Keyword(s):  
Drug Disposition ◽  
Geometric Mean ◽  
Latin Square ◽  
Dried Blood Spots ◽  
Pharmacokinetic Parameters ◽  
Geometric Mean Ratio ◽  
Glycoprotein P ◽  
Drug Concentrations ◽  
Simultaneous Evaluation ◽  
The Impact

Drug metabolic enzymes and transporters are responsible for an important variability in drug disposition. The cocktail approach is a sound strategy for the simultaneous evaluation of several enzyme and transporter activities for a personalized dosage of medications. Recently, we have demonstrated the reliability of the Geneva cocktail, combining the use of dried blood spots (DBS) and reduced dose of phenotyping drugs for the evaluation of the activity of six cytochromes and P-glycoprotein (P-gp). As part of a study evaluating potential drug–drug interactions between probe drugs of the Geneva cocktail, the present paper focuses on the impact of cytochromes (CYP) probe drugs on the disposition of fexofenadine, a P-gp test drug. In a randomized four-way Latin-square crossover study, 30 healthy volunteers (15 men and 15 women) received caffeine 50 mg, bupropion 20 mg, flurbiprofen 10 mg, omeprazole 10 mg, dextromethorphan 10 mg, midazolam 1 mg, and fexofenadine 25 mg alone (or as part of a previously validated combination) and all together (Geneva cocktail). The determination of drug concentrations was performed in DBS samples and pharmacokinetic parameters were calculated. Fexofenadine AUC0–8 h and Cmax decreased by 43% (geometric mean ratio: 0.57; CI 90: 0.50–0.65; p < 0.001) and 49% (geometric mean ratio: 0.51; CI 90: 0.44–0.59; p < 0.001), respectively, when fexofenadine was administered as part of the Geneva cocktail in comparison to fexofenadine alone. Consequently, the apparent oral clearance (Cl/F) increased 1.7-fold (CI 90: 1.49–1.93; p < 0.001). There was no interaction between the remaining probes. In conclusion, an unexpected interaction occurred between fexofenadine and one or several of the following substances: caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam. Further studies are necessary to elucidate the mechanism of this interaction.

scholarly journals Intestinal Absorption of Geniposide and Inhibition of Transporter-P-GP Across the Caco-2 Monolayer

2020 ◽  
Author(s):  
Yanhong Bu ◽  
hong wu ◽  
MingHui Sun ◽  
Heng Zhang ◽  
Ran Deng ◽  
...  
Keyword(s):  
Intestinal Absorption ◽  
Cell Monolayer ◽  
Hplc Method ◽  
Transepithelial Transport ◽  
Absolute Bioavailability ◽  
Glycoprotein P ◽  
Gardenia Jasminoides ◽  
P Glycoprotein ◽  
Bioactive Component ◽  
Bidirectional Transport

Abstract Background: Geniposide (GE) is the main bioactive component of Gardenia jasminoides Ellis, which has many pharmacological effects, such as anti-inflammatory, anti-oxidation, and anti-angiogenesis. GE has low absolute bioavailability after oral administration, and speculated that GE might have an effect on P-glycoprotein (P-gp) described in our previous study. However, intestinal absorption characteristics involved in the Caco-2 cells of GE are still unknown. Therefore, we aimed to investigate absorption mechanisms of GE and the effects on P-gp. Methods: By establishing the Caco-2 cells model and HPLC method, bidirectional transport of GE in the different conditions and the presence of P-gp inhibitors－verapamil were conducted to observe its absorption mechanisms. Transport assays of digoxin, a P-gp substrate, were also performed in the presence of GE or verapamil. The effects of GE on the function and expression of P-gp were analyzed by flow cytometry and Western blot using rhodamine-123 (rho-123) and the antibody, respectively. Results: Both absorption and secretion of GE were positively correlated with concentration and time at Caco-2 cell monolayer. The Papp of bidirectional transport was decreased in low temperature and the Papp(BL-AP) of GE decreased significantly in the presence of verapamil. Meanwhile, the ER value was higher than 1.5. In addition, in the bidirectional transport of digoxin, the values of Papp(BL-AP) and ER decreased significantly in the presence of GE, just like verapamil. GE increased the intracellular accumulation of rho-123 and also have a significant decrease on P-gp expression. Conclusion: Transepithelial transport mechanism of GE in Caco-2 cell monolayer is mainly passive diffusion and P-gp mediated active transportation. GE was a potential inhibitor of P-gp, can inhibit transport of digoxin and the function and expression of P-gp.

Correlation between P-glycoprotein (P-gp) expression in parathyroid and Tc-99m MIBI parathyroid image findings

2001 ◽  
Vol 28 (8) ◽  
pp. 929-933 ◽  
Author(s):  
Shung-Shung Sun ◽  
Yu-Chien Shiau ◽  
Cheng-Chieh Lin ◽  
Albert Kao ◽  
Cheng-Chun Lee
Keyword(s):  
Glycoprotein P ◽  
P Glycoprotein

Molecular docking studies of tea (Thea sinensis Linn.) polyphenols inhibition pattern with Rat P-glycoprotein

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Babar Ali ◽  
Qazi Mohammad Sajid Jamal ◽  
Showkat R. Mir ◽  
Saiba Shams ◽  
Mohammad Amjad Kamal
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Binding Energy ◽  
Oral Administration ◽  
Docking Studies ◽  
Vital Role ◽  
Glycoprotein P ◽  
High Affinity ◽  
P Glycoprotein ◽  
Inhibition Pattern

AbstractSince 3000 B.C., evergreen plant Thea sinensis (Theaceae) is used both as a social and medicinal beverage. Leaves of T. sinensis contain amino acids, vitamins, caffeine, polysaccharides and polyphenols. Most of the natural medicinal actions of tea are due to the availability and abundance of polyphenols mainly catechins. It has also been stated that some catechins were absorbed more rapidly than other compounds after the oral administration of tea and could increase the bio-enhancing activities of anticancer drugs by inhibiting P-glycoprotein (P-gp). The results of the molecular docking showed that polyphenols bind easily to the active P-gp site. All compounds exhibited fluctuating binding affinity ranged from −11.67 to −8.36 kcal/mol. Observed binding energy required for theaflavin to bind to P-gp was lowest (−11.67 kcal/mol). The obtained data that supports all the selected polyphenols inhibited P-gp and therefore may enhance the bioavailability of drugs. This study may play a vital role in finding hotspots in P-gp and eventually may be proved useful in designing compounds with high affinity and specificity to the protein.

scholarly journals Co-Amorphous Formulations of Furosemide with Arginine and P-Glycoprotein Inhibitor Drugs

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 171
Author(s):  
Marika Ruponen ◽  
Konsta Kettunen ◽  
Monica Santiago Pires ◽  
Riikka Laitinen
Keyword(s):  
Storage Conditions ◽  
Scanning Calorimetry ◽  
Glycoprotein P ◽  
Molar Ratios ◽  
P Glycoprotein ◽  
Permeation Studies ◽  
Poorly Soluble ◽  
Biopharmaceutics Classification ◽  
Permeability Assay ◽  
Simultaneous Dissolution

In this study, the amino acid arginine (ARG) and P-glycoprotein (P-gp) inhibitors verapamil hydrochloride (VER), piperine (PIP) and quercetin (QRT) were used as co-formers for co-amorphous mixtures of a Biopharmaceutics classification system (BCS) class IV drug, furosemide (FUR). FUR mixtures with VER, PIP and QRT were prepared by solvent evaporation, and mixtures with ARG were prepared by spray drying in 1:1 and 1:2 molar ratios. The solid-state properties of the mixtures were characterized with X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) in stability studies under different storage conditions. Simultaneous dissolution/permeation studies were conducted in side-by-side diffusion cells with a PAMPA (parallel artificial membrane permeability assay) membrane as a permeation barrier. It was observed with XRPD that ARG, VER and PIP formed co-amorphous mixtures with FUR at both molar ratios. DSC and FTIR revealed single glass transition values for the mixtures (except for FUR:VER 1:2), with the formation of intermolecular interactions between the components, especially salt formation between FUR and ARG. The co-amorphous mixtures were found to be stable for at least two months under an elevated temperature/humidity, except FUR:ARG 1:2, which was sensitive to humidity. The dissolution/permeation studies showed that only the co-amorphous FUR:ARG mixtures were able to enhance both the dissolution and permeation of FUR. Thus, it is concluded that formulating co-amorphous salts with ARG may be a promising option for poorly soluble/permeable FUR.

scholarly journals Pulchinenosides from Pulsatilla Chinensis Increase P-Glycoprotein Activity and Induce P-Glycoprotein Expression

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yali Liu ◽  
Ling Zhang ◽  
Shaofeng Wei ◽  
Jinyang Cai ◽  
Zhenzhong Zang ◽  
...  
Keyword(s):  
Membrane Vesicles ◽  
Pcr Analysis ◽  
Mrna Levels ◽  
Intestinal Epithelial ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Human Intestinal Epithelial Cells ◽  
Pulsatilla Chinensis ◽  
Dependent Transport ◽  
Cytotoxic Studies

Five pulchinenosides (pulchinenoside B3, pulchinenoside BD, pulchinenoside B7, pulchinenoside B10, and pulchinenoside B11) isolated from Pulsatilla chinensis (Bge) Regel saponins extract exhibited strong antitumor activities but poor gastrointestinal absorption properties. The enteric induction of P-glycoprotein (P-gp) is understood to restrict the oral bioavailability of some pharmaceutical compounds and lead to adverse drug reactions. Therefore, the present investigation was intended to delineate the impacts of pulchinenosides on cellular P-gp function and expression using Sf9 membrane vesicles and LS180 cells as a surrogate of human intestinal epithelial cells. Preliminary cytotoxic studies showed that 10 μM was an acceptable concentration for cytotoxicity and antiproliferation studies for all pulchinenosides using the alamarBlue assay. The cell cycle of LS180 cells detected by flow cytometry was not significantly influenced after 48 hours of coincubation with 10 μM of pulchinenosides. In the presence of pulchinenosides, the ATP-dependent transport of N-methyl-quinidine mediated by P-glycoprotein was stimulated significantly. The upregulation of P-glycoprotein and mRNA levels was found by Western blot and real-time PCR analysis in LS180 cells. Parallel changes indicate that all pulchinenosides are exposed to pulchinenosides-mediated transcriptional regulation. In conclusion, pulchinenosides could induce P-glycoprotein expression and directly increase its functional activity.

Evaluation of the Impact of P-Glycoprotein (P-gp) Drug Efflux Transporter Blockade on the Systemic and Ocular Disposition of P-gp Substrate

2008 ◽  
Vol 24 (3) ◽  
pp. 290-300 ◽  
Author(s):  
Srinivasan Senthilkumari ◽  
Thirumurthy Velpandian ◽  
Nihar R. Biswas ◽  
Narayanan Sonali ◽  
Supriyo Ghose
Keyword(s):  
Drug Efflux ◽  
Efflux Transporter ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
The Impact

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.

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