Role of Transporters in Drug Development

Arya, Vikram; Kiser, Jennifer J.

doi:10.1002/jcph.784

Cited by 8 publications

(10 citation statements)

References 45 publications

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“…During drug metabolism, drugs arrive in liver cells via blood circulation, and hence initial drug transport into the hepatocytes begun via influx transporters [24]. e drug in the form of the parent drug is metabolized by phase I and II drug-metabolizing enzymes (DMEs) and products of many reactive metabolites [25]. Phase I metabolism mainly includes cytochrome P450-1 and P450-2 (CYP1 and CYP2) and flavin-containing monooxygenases (FMO) [26].…”

Section: Pathophysiology Of Dilimentioning

confidence: 99%

Potential Effects of Dietary Isoflavones on Drug-Induced Liver Injury

Yao

Nisar

Yan

et al. 2021

Journal of Food Quality

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Numerous prescribed drugs and herbal and dietary supplements have been reported to cause drug-induced acute liver injury, which is a frequent cause of acute liver failure (ALF). It is a tremendous challenge with ever-increasing drug application in the medication system for huge populations. Drug-induced acute liver injury can lead to diverse pathologies similar to acute and chronic hepatitis, acute liver failure, biliary obstruction, fatty liver disease, and so on. Recently, extensive work demonstrated that isoflavones play an essential and protecting role in drug-induced liver injury (DILI). The isoflavones mediated hepatoprotection by modulating specific genes linked with control of cellular redox homeostasis and inflammatory responses. Isoflavones upregulate oxidative stress-responsive nuclear factor erythroid 2-like 2 (Nrf2), downregulate inflammatory nuclear factor-κB (NF-κB) signaling pathways, and modulate a balance between cell survival and death. Moreover, isoflavones actively inhibit the expression of cytochromes P450 (CYPs) enzyme during drug metabolism. Moreover, isoflavones are also linked with farnesoid X receptor (FXR) activation and signal transducer and activator of transcription factor 3 (STAT3) phosphorylation in hepatoprotection DILI. In vivo and in vitro studies clearly stated that isoflavones bear strong antioxidant potential and promising agents for hepatotoxicity prevention and stressed their potential role as therapeutic supplements in DILI. The current review will elaborate on isoflavones’ preventive and therapeutic potential concisely and highlight various molecular targets to exert a protective effect on DILI.

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Section: Pathophysiology Of Dilimentioning

confidence: 99%

Potential Effects of Dietary Isoflavones on Drug-Induced Liver Injury

Yao

Nisar

Yan

et al. 2021

Journal of Food Quality

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“…Our study shows that the combination of PET studies with PBPK modeling could be a useful tool to better understand and predict transporter-mediated DDIs in tissues. 3,36…”

Section: Resultsmentioning

confidence: 99%

A Prediction Method for P-glycoprotein–Mediated Drug–Drug Interactions at the Human Blood–Brain Barrier From Blood Concentration–Time Profiles, Validated With PET Data

Matsuda

Karch

Bauer

et al. 2017

Journal of Pharmaceutical Sciences

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The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration-time profiles and P-glycoprotein (Pgp)-mediated brain drug-drug interactions between the model Pgp substrate (R)-[C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [C]tariquidar (TQD), and the Pgp inhibitor tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration-time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration-time profiles and rank the magnitude of the Pgp-mediated brain drug-drug interaction potential for both Pgp and Pgp/BCRP substrates in humans.

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“…To reduce FN predictions, in addition to reducing IC 50 or K i variability, one also needs to consider other possible mechanisms that may contribute to in vivo DDI between a particular drug with digoxin, for example, the contribution of additional transporters (eg, organic anion-transporting polypeptides) and inhibitory metabolites, as discussed in multiple publications. 4,18,26 Similarly, the analysis of the possible reasons underlying the FP predictions would improve our understanding on the prediction methods ( Table 4). The overestimation of intestinal drug concentration appeared to be the major reason for FPs because 9 of the 10 drugs with FP predictions had low solubility (belong to Category 1) ( Table 4).…”

Section: Discussionmentioning

confidence: 99%

“…The limitation of these prediction methods is that they only consider P‐gp inhibition and parent drugs as the inhibitor. To reduce FN predictions, in addition to reducing IC 50 or K i variability, one also needs to consider other possible mechanisms that may contribute to in vivo DDI between a particular drug with digoxin, for example, the contribution of additional transporters (eg, organic anion‐transporting polypeptides) and inhibitory metabolites, as discussed in multiple publications …”

Section: Discussionmentioning

confidence: 99%

Comparing Various In Vitro Prediction Methods to Assess the Potential of a Drug to Inhibit P‐glycoprotein (P‐gp) Transporter In Vivo

Zhou

Arya

Zhang

2019

The Journal of Clinical Pharma

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The evaluation of potential of a new molecular entity (NME) to inhibit P-glycoprotein (P-gp) in vivo is an integral part of drug development and is recommended by regulatory agencies. In this study, we compared the performance of 5 prediction methods and their associated criteria (including those from the European Medicines Agency, the US Food and Drug Administration, and the Pharmaceuticals and Medical Devices Agency of Japan) for assessing the potential of an NME to inhibit P-gp in vivo based on in vitro assessment. We collected in vitro (eg, half-maximal inhibitory concentration [IC 50 ], fraction unbound to plasma protein) and in vivo (eg, dose, maximum concentration, change in maximum concentration or area under the plasma concentration-time curve of the substrate digoxin) data for 50 Food and Drug Administration-approved, orally administered drug products containing 53 NMEs, from the University of Washington Metabolism and Transport Drug Interaction Database, Drugs@FDA, and PubMed. All methods yielded similar accuracy with small differences in false-negative (FN) and false-positive (FP) predictions. In addition, use of ratio of the theoretical maximum gastrointestinal concentration to IC 50 is sufficient for a reasonable prediction for these orally administered drugs as potential P-gp inhibitors based on our dataset. The FN and FP rates varied depending on the cut-off value for the ratio of the theoretical maximum gastrointestinal concentration/IC 50 . Possible reasons underlying FP and FN results from different methods should be taken into consideration to predict in vivo P-gp inhibition.

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Role of Transporters in Drug Development

Cited by 8 publications

References 45 publications

Potential Effects of Dietary Isoflavones on Drug-Induced Liver Injury

Potential Effects of Dietary Isoflavones on Drug-Induced Liver Injury

A Prediction Method for P-glycoprotein–Mediated Drug–Drug Interactions at the Human Blood–Brain Barrier From Blood Concentration–Time Profiles, Validated With PET Data

Comparing Various In Vitro Prediction Methods to Assess the Potential of a Drug to Inhibit P‐glycoprotein (P‐gp) Transporter In Vivo

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