An Introduction to P-Glycoprotein


Wahajuddin, PhD, FHEA, FRSB, FRSC (Editor) – Principal Scientist, CSIR-Central Drug Research Institute, Lucknow (U.P.), India
Ravindra Varma Alluri, PhD (Editor) – Associate Principal Scientist, Clinical Pharmacology and Safety Sciences, AstraZeneca R&D, Cambridge, UK
Rahul Dev Jayant, PhD (Editor) – Assistant Professor, Texas Tech University Health Sciences Center, Texas, USA

Series: Pharmacology – Research, Safety Testing and Regulation

BISAC: MED071000

Target Audience: Students, Researchers, Teachers, Professors, Professionals in higher education and research dealing with Biology, Medicine, Therapeutics, Toxicology, Pharmacy, Pharmacology, Pharmaceutical Sciences, Medicine Safety and Regulatory Affairs, Pharmaceutical Medicine, Life Science, Biotechnology, Biomedicine, Paramedical, Public Health, Allied Biomedical Sciences, Bioinformatics and Structural Biology.

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.




Chapter 1. Introduction: Structure and Function
(Anupam Dhasmana, Sudhir Kotnala, Murali M. Yallapu, Subhash C. Chauhan and Meena Jaggi – Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, US, et al.)

Chapter 2. Relative Distribution of P-Glycoprotein (P-gp) and its Pharmacological Relevance
(Nishant S. Kulkarni, Snehal K. Shukla and Vivek Gupta – Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences,St. John’s University, Queens, NY, US)

Chapter 3. P-gp Pathophysiology: Post-Translational Modification and Affecting Signaling Cascades
(Sree-Pooja Varahachalam, Jaspreet Kaur, Minitha Jacob, Behnaz Lahooti, Tanya Chhibber, Alexis Hyman, Abhijeet Joshi and Rahul Dev Jayant – Department of Pharmaceutical Sciences, JH School of Pharmacy, Texas Tech University Health Science Center, Amarillo, TX, USA, et al.)

Chapter 4. Mechanistic Comprehension towards the Role of P-Glycoprotein in Limiting the Pharmacokinetic and Pharmacological Efficacy of Drugs
(Swati Chaturvedi, Nazneen Sultana, Mamunur Rashid, Divya Chauhan, Zaiba Naseem, Ravindra V. Alluri and Wahajuddin – Pharmaceutics and Pharmacokinetics Division, CSIR- Central Drug Research Institute, Lucknow, India, et al.)

Chapter 5. P-Glycoprotein, a Biological and Medicinal Chemistry/Radiochemistry Point of View
(Carmen Abate, Nicola Antonio Colabufo and Marialessandra Contino – Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, Bari, Italy)

Chapter 6. P-Glycoprotein: A New Insight in the Field of Neurogenesis with a Different Perspective
(Virendra Tiwari, Akanksha Mishra, Sonu Singh and Shubha Shukla – Neuroscience and Ageing Biology Division, CSIR- Central Drug Research Institute, (U.P.), India, et al.)

Chapter 7. Formulation Strategies to Bypass P-Glycoprotein Mediated Drug Efflux
(Viral Shah and Manish Nivsarkar – Dept. of Pharmaceutics, B. V. Patel, Pharmaceutical Education and Research Centre, Ahmedabad, Gujarat, India, et al.)

Chapter 8 Marine Sources Potentiate to Inhibit P-Glycoprotein for the Management of Cancers and Multidrug Resistance
(Varish Ahmad, Qazi Mohammad Sajid Jamal, Sohail Akhtar, Aftab Ahmad, Zaiba Naseem, Mohammed F. Abuzinadah and Shahid Karim – Health Information Technology Department, Faculty of Applied Studies, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia, et al.)

Chapter 9. P-Glycoprotein and Its Association in Neurodegenerative Disorders
(Himani Panwar, Anushruti Ashok, Swati Chaturvedi, Ranjay Kumar Chaudhary, Arti Thakur and Sadaf Jahan – Gurukul Kangri Vishwavidyalaya, Haridwar, Uttarakhand, India, et al.)

Chapter 10. P-Glycoprotein Polymorphism: Genetic and Epigenetic Changes
(Tarique Mahmood Ansari, Mohammad Haris Siddiqui, Malik Mobeen, Farogh Ahsan and Arshiya Shamim – Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, et al.)

Chapter 11. Quantification and Analysis of P-Glycoprotein: In Vitro, In Situ, and In Vivo Models
(Deepak S. Chauhan, Meena Jaggi, Subhash C. Chauhan and Murali M. Yallapu – Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, US, South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, US)

Chapter 12. Recent Advancements and Future Perspectives
(Nazneen Sultana, Swati Chaturvedi, Divya Chauhan and Wahajuddin – Pharmaceutics and Pharmacokinetics Division, CSIR – Central Drug Research Institute, Lucknow, Uttar Pradesh, India, et al.)


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