In Vitro Techniques to Study Drug–Drug Interactions Involving Transport: Caco-2 Model for Study of P-Glycoprotein and Other Transporters

2009 ◽  
pp. 257-282 ◽  
Author(s):  
William R. Proctor ◽  
Xin Ming ◽  
Dhiren R. Thakker
Keyword(s):  
Drug Interactions ◽  
Study Drug ◽  
In Vitro Techniques ◽  
P Glycoprotein

scholarly journals In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4589 ◽  
Author(s):  
Sunjoo Kim ◽  
Dong Kyun Kim ◽  
Yongho Shin ◽  
Ji-Hyeon Jeon ◽  
Im-Sook Song ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Liver Microsomes ◽  
Drug Abusers ◽  
Cancer Resistance ◽  
Mixed Inhibition ◽  
P Glycoprotein ◽  
Human Cytochrome

AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug–drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated. AB-FUBINACA inhibited CYP2B6-mediated bupropion hydroxylation via mixed inhibition with Ki value of 15.0 µM and competitively inhibited CYP2C8-catalyzed amodiaquine N-de-ethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation, and CYP2D6-catalyzed bufuralol 1′-hydroxylation with Ki values of 19.9, 13.1, 6.3, and 20.8 µM, respectively. AB-FUBINACA inhibited OCT2-mediated MPP+ uptake via mixed inhibition (Ki, 54.2 µM) and competitively inhibited OATP1B1-mediated estrone-3-sulfate uptake (Ki, 94.4 µM). However, AB-FUBINACA did not significantly inhibit CYP1A2, CYP2A6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 enzyme activities at concentrations up to 100 µM. AB-FUBINACA did not significantly inhibit the transport activities of OCT1, OAT1/3, OATP1B3, P-glycoprotein, or BCRP at concentrations up to 250 μM. As the pharmacokinetics of AB-FUBINACA in humans and animals remain unknown, it is necessary to clinically evaluate potential in vivo pharmacokinetic drug–drug interactions induced by AB-FUBINACA-mediated inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, OCT2, and OATP1B1 activities.

20(S)-Ginsenoside Rh2 Noncompetitively Inhibits P-Glycoprotein In Vitro and In Vivo: A Case for Herb-Drug Interactions

2010 ◽  
Vol 38 (12) ◽  
pp. 2179-2187 ◽  
Author(s):  
Jingwei Zhang ◽  
Fang Zhou ◽  
Xiaolan Wu ◽  
Yi Gu ◽  
Hua Ai ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Ginsenoside Rh2 ◽  
P Glycoprotein

The Utility of In Vitro Data in Making Accurate Predictions of Human P-Glycoprotein-Mediated Drug-Drug Interactions: A Case Study for AZD5672

2010 ◽  
Vol 39 (2) ◽  
pp. 275-282 ◽  
Author(s):  
Robert Elsby ◽  
Michael Gillen ◽  
Caroline Butters ◽  
Gemma Imisson ◽  
Pradeep Sharma ◽  
...  
Keyword(s):  
Drug Interactions ◽  
P Glycoprotein ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals Exposure of LS-180 Cells to Drugs of Diverse Physicochemical and Therapeutic Properties Up-regulates P-glycoprotein Expression and Activity

2011 ◽  
Vol 14 (2) ◽  
pp. 236 ◽  
Author(s):  
Alaa H Abuznait ◽  
Shawn G Patrick ◽  
Amal Kaddoumi
Keyword(s):  
Drug Interactions ◽  
Drug Disposition ◽  
Rank Order ◽  
Gene Expressions ◽  
Experimental Conditions ◽  
P Glycoprotein ◽  
Therapeutic Properties ◽  
Expression And Activity

Purpose. Drug transporters are increasingly recognized as important determinants of variability in drug disposition and therapeutic response, both in pre-clinical and clinical stages of drug development process. The role P-glycoprotein (P-gp) plays in drug interactions via its inhibition is well established. However, much less knowledge is available about drugs effect on P-gp up-regulation. The objective of this work was to in vitro investigate and rank commonly used drugs according to their potencies to up-regulate P-gp activity utilizing the same experimental conditions. Methods. The in vitro potencies of several drugs of diverse physicochemical and therapeutic properties including rifampicin, dexamethasone, caffeine, verapamil, pentylenetetrazole, hyperforin, and β-estradiol over broad concentration range to up-regulate P-gp expression and activity were examined. For dose-response studies, LS-180 cells were treated with different concentrations of the selected drugs followed by P-gp protein and gene expressions analyses. P-gp functionality was determined by uptake studies with rhodamine 123 as a P-gp substrate, followed by Emax/EC50 evaluation. Results. The results demonstrated a dose-dependent increase in P-gp expression and activity following treatments. At 50 uM concentration (hyperforin, 0.1 uM), examined drugs increased P-gp protein and gene expressions by up to 5.5 and 6.2-fold, respectively, while enhanced P-gp activity by 1.8-4-fold. The rank order of these drugs potencies to up-regulate P-gp activity was as following: hyperforin >>> dexamethasone ~ beta-estradiol > caffeine > rifampicin ~ pentylenetetrazole > verapamil. Conclusions. These drugs have the potential to be involved in drug interactions when administered with other drugs that are P-gp substrates. Further studies are needed to in vivo evaluate these drugs and verify the consequences of such induction on P-gp activity for in vitro-in vivo correlation purposes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Development of a Microfluidic Array to Study Drug Response in Breast Cancer

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4385
Author(s):  
Virumbrales-Muñoz ◽  
Livingston ◽  
Farooqui ◽  
Skala ◽  
Beebe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Cells ◽  
Study Drug ◽  
Cell Types ◽  
Micro Milling ◽  
In Vitro Techniques ◽  
Chemotherapy Drugs ◽  
Breast Cancer Invasion ◽  
Lower Permeability

Luminal geometries are common structures in biology, which are challenging to mimic using conventional in vitro techniques based on the use of Petri dishes. In this context, microfluidic systems can mimic the lumen geometry, enabling a large variety of studies. However, most microfluidic models still rely on polydimethylsiloxane (PDMS), a material that is not amenable for high-throughput fabrication and presents some limitations compared with other materials such as polystyrene. Thus, we have developed a microfluidic device array to generate multiple bio-relevant luminal structures utilizing polystyrene and micro-milling. This platform offers a scalable alternative to conventional microfluidic devices designed in PDMS. Additionally, the use of polystyrene has well described advantages, such as lower permeability to hydrophobic molecules compared with PDMS, while maintaining excellent viability and optical properties. Breast cancer cells cultured in the devices exhibited high cell viability similar to PDMS-based microdevices. Further, co-culture experiments with different breast cell types showed the potential of the model to study breast cancer invasion. Finally, we demonstrated the potential of the microfluidic array for drug screening, testing chemotherapy drugs and photodynamic therapy agents for breast cancer.

Inhibitory effects of herbal constituents on P-glycoprotein in vitro and in vivo: Herb–drug interactions mediated via P-gp

2014 ◽  
Vol 275 (2) ◽  
pp. 163-175 ◽  
Author(s):  
Xue Li ◽  
Jinping Hu ◽  
Baolian Wang ◽  
Li Sheng ◽  
Zhihao Liu ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Inhibitory Effects ◽  
P Glycoprotein
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