An introduction to p-glycoprotein / M. Wahajuddin, Ravindra Varma Alluri and Rahul Dev Jayant (editors).

Format:

Book

Contributor:

Dev Jayant, Rahul, editor.

Varma Alluri, Ravindra, editor.

Wahajuddin, M., editor.

Series:

Pharmacology - Research, Safety Testing and Regulation

Language:

English

Subjects (All):

Drug resistance in cancer cells.

P-glycoprotein.

Physical Description:

1 online resource (408 pages)

Place of Publication:

New York, New York : Nova Science Publishers, [2021]

Summary:

"P-glycoprotein (P-gp), encoded by the multidrug-resistance (MDR)-1 gene is one of the best studied efflux transporters that is linked to multidrug resistance in cancer chemotherapies. P-gp belongs to the ATP-binding cassette (ABC) transporter family of proteins that utilizes energy derived from hydrolysis of ATP to efflux endogenous and exogenous xenobiotics, metabolites and toxins from the intracellular space to the outside, thereby providing a general protective role. P-gp is expressed on the apical plasma membrane of all major drug eliminating organs such as the intestine (enterocytes), liver (bile canaliculi), kidney (proximal tubules), brain (endothelia of blood-brain barrier) and in certain tumor types. In the intestine and BBB, P-gp limits entry of drugs by actively pumping drugs back into the lumen or blood, respectively. In the liver and kidney, P-gp actively effluxes drugs, endogenous substances and metabolites into bile or urine, thereby removing them from the body. Upregulation of P-gp in tumor cells is noted in several cancers and is a hallmark for drug resistance. Additionally, P-gp is also shown to play a role in neurogenesis and maintaining homeostasis in the brain. Alteration of P-gp expression is observed in neurodegenerative diseases, highlighting its importance in maintaining normal brain health. Due to its central role in defining oral pharmacokinetics, systemic clearance, tissue exposure, organ health and chemoresistance, much of the research has been focused on modulating P-gp. Chemical inhibitors, formulation-based and epigenetic approaches are applied to modulate P-gp activity with a goal to improve oral pharmacokinetics, increase tumor and brain penetration, minimize organ toxicity and potentially treat neurodegenerative diseases. Although enormous research on P-gp has been published, a book chapter exclusively and comprehensively covering diverse aspects of P-gp, including the recent developments in the field, is required. With much enthusiasm from the publisher, we have collaborated to bring together wide-ranging topics on P-gp. This book contains 12 chapters covering the structure, function, regulation, distribution and expression of P-gp, its pharmacological importance in health and disease and role in pharmacokinetics and drug-drug interactions. Also included are computational approaches to identify selective inhibitors and tactics to modulate P-gp function using chemical inhibitors (synthesized or isolated from marine sources), formulation strategies or epigenetic approaches. The last chapter describes various methods to quantify P-gp expression levels and function in in vitro, in situ and in vivo settings. It is our sincere hope that this material will serve as an important desk reference for students, researchers and clinical scientists in academia, medical research and the pharmaceutical industry working in various fields such as pharmacology, pharmacy, toxicology, medicinal chemistry, pharmaceutical sciences, pharmacokinetics and computational biology"-- Provided by publisher.

Contents:

Intro

Contents

Preface

Acknowledgments

Chapter 1

Introduction: Structure and Function

Abstract

Introduction

Structure

Topological Features of P-gp

Functions of P-Glycoprotein

Potential Mechanism of Action for Drug Disposition by P-Glycoprotein (P-gp)

Molecular and Biological Functions of P-gp

Role of P-gp in Various Pathologies

Interactome Analysis of P-Gp and Associated Metabolic Pathways Using Protein Interaction Analysis and Pathway Enrichment Analysis

Conclusion and Future Perspectives

References

Chapter 2

Relative Distribution of P-glycoprotein (P-gp) and its Pharmacological Relevance

Physiological Distribution of P-glycoprotein in Normal and Diseased Conditions

Intestinal Epithelium

Liver

Kidneys

Blood-Brain Barrier (BBB)

Pharmacokinetics and Pharmacological Relevance

Efflux Mechanisms and Effect of P-gp in Oral Bioavailability

Efflux Mechanisms

Effect on Oral Bioavailability

Cerebral Disorders

Alzheimer's Disease

Epilepsy

Tumors

Ovarian Cancer

Autoimmune Disorders

Systemic Lupus Erythematosus (SLE)

Rheumatoid Arthritis

Role of P-gp in Development of Multidrug Resistance (MDR)

Conclusion

Declaration of Competing Interests

Chapter 3

P-gp Pathophysiology:

Post-Translational Modification

and Affecting Signaling Cascades

P-gp as a Lipid Flippase

P-gp as a Vacuum Cleaner

Effect of P-gp in Pathology

Pathophysiology of Various Diseases Related to P-gp

Signaling Transduction

Pathway of P-gp Intracellular Trafficking

Post-translational Moifications of Transporters

Chapter 4.

Mechanistic Comprehension towards the Role of P-Glycoprotein in Limiting the Pharmacokinetic and Pharmacological Efficacy of Drugs

Introduction and Background

Structure and Function of P-gp

P-gp and Drug Pharmacokinetics/Bioavailability

Effect of P-gp on Drug Absorption

Effect of P-gp Upon Drug Distribution

Effect of P-gp Upon Drug Metabolism

Effect of P-gp Upon Drug Elimination

Pathophysiology Behind P-gp and Drug Interaction

Conflict of Interest

Chapter 5

P-Glycoprotein, a Biological and Medicinal Chemistry/Radiochemistry Point of View

A Biological Point of View: The P-Gp Interacting Mechanism

Substrates, Inhibitors and Modulators: The Pivotal Role of P-Gp in the Therapy and Diagnosis of Pathological Conditions

P-Glycoprotein Inducers and Activators

A Medicinal Chemistry Point of View: Development of P-gp Interacting Compounds

P-Gp Radiotracers

P-gp Substrates

P-gp Inhibitors

Chapter 6

P-Glycoprotein: A New Insight in

the Field of Neurogenesis with

a Different Perspective

Neurogenesis and Its Regulation

Factors Regulating Neurogenesis

P-glycoprotein

Involvement of P-Glycoprotein in Neurodegeneration

Link Between P-Glycoprotein and Neurogenesis

Conclusion and Future Prospects

Chapter 7

Formulation Strategies to Bypass P-Glycoprotein Mediated Drug Efflux

P-gp Efflux Transporter Structure and Mechanism of Action

P-gp Substrates and Inhibitors

Drug Delivery Strategies to Bypass P-Glycoprotein Mediated Drug Efflux.

Pharmaceutical Excipients Used In Drug Delivery Systems as P-gp Inhibitors

Natural Polymers

Synthetic Polymers

Solvents and Surfactants

Formulations with P-gp Modulatory Applications

Self-Emulsifying Drug Delivery Systems

Double Coated Nanocapsules for Enhanced Intestinal Absorption and Bioavailability of a P-gp Substrate

Nanocarriers

Polymeric Micelles

Polyethylene Glycol-660 Hydroxystearate Nanocapsules

Immunoliposomes

Dendrimers

Poly(D,L-lactide) Nanosuspensions

Exosomes

Chapter 8

Marine Sources Potentiate to Inhibit P-Glycoprotein for the Management of Cancers and Multidrug Resistance

1. Introduction

2. Mechanism of the Drug Resistance

3. Chemical Nature of Marine-Derived P-gp Inhibitors

4. Microorganisms as Sources of P-Glycoproteins

4.1. P-gp Inhibitors from Sponge

4.2. P-gp Inhibitors from Bryozoans

4.3. P-gp Inhibitors from Corals

4.4. P-gp Inhibitors from Algae

4.5. P-gp Inhibitors from Bacteria and Fungi

4.6. P-gp Inhibitors from Mollusk

4.7. Inhibitors from Tunicates

Chapter 9

P-Glycoprotein and Its Association in Neurodegenerative Disorders

Blood Brain Barrier and P-gp Location

Background Knowledge about P-gp

Role of P-gp in Neurodegenerative Disorders

Alzheimer Disease (AD)

Parkinson Disease (PD)

Amyotrophic Lateral Sclerosis (ALS)

Stroke

Future Aspects

Conflict of interest

Chapter 10

P-Glycoprotein Polymorphism: Genetic and Epigenetic Changes

Role of MDR1 Gene in Pgp Polymorphism

Role of ATP-Binding Cassette-B1 (ABCB1) in Pgp Polymorphism

Epigenetic Role of P-Glycoprotein in Alteration of Pharmacokinetics.

Compounds that Epigenetically Interact with P-gp

Drug Interactions

Drug Interactions Leading to Epigenetic Changes

Chapter 11

Quantification and Analysis of P-Glycoprotein: In Vitro, In Situ, and In Vivo Models

In Vitro Methods

Culture Modified

Sandwich Cultured Hepatocytes

Side by Side Diffusion Chambers

In Situ Methods

Perfused Intestine

Perfused Liver

In Vivo Methods

[11C]Verapamil and [11C]D617

[11C]Desmethy-Loperamide and[11C]Loperamide

[11C]Colchicine

[11C]Daunorubicin

[11C]Paclitaxel

[11C]Docetaxel

[11C]Carvedilol

[11C]Laniquidar

[11C]Elacridar

[11C]Tariquidar

Chapter 12

Recent Advancements and Future Perspectives

Reversal of MDR by Novel P-gp Inhibitors

Nanotechnology Strategy to Combat P-gp Mediated MDR

Third Generation Small Molecule P-gp Inhibitor

P-gp Inhibitors from Natural Products Extracts

About the Editors

Index

Blank Page.

Notes:

Description based on print version record.

Includes bibliographical references and index.

ISBN:

1-5361-9728-9

OCLC:

1252740035