Abstract
Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the ‘victim’ drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk.
Keywords: CYP, Cytochrome P450, drug-drug interaction, inactivation, inhibition, time-dependent inactivation
Current Topics in Medicinal Chemistry
Title: Assessment of Cytochrome P450 Enzyme Inhibition and Inactivation in Drug Discovery and Development
Volume: 11 Issue: 4
Author(s): David O. Nettleton and Heidi J. Einolf
Affiliation:
Keywords: CYP, Cytochrome P450, drug-drug interaction, inactivation, inhibition, time-dependent inactivation
Abstract: Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the ‘victim’ drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk.
Export Options
About this article
Cite this article as:
O. Nettleton David and J. Einolf Heidi, Assessment of Cytochrome P450 Enzyme Inhibition and Inactivation in Drug Discovery and Development, Current Topics in Medicinal Chemistry 2011; 11 (4) . https://dx.doi.org/10.2174/156802611794480882
DOI https://dx.doi.org/10.2174/156802611794480882 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Effectiveness and Safety of Baclofen in the Treatment of Alcohol Dependent Patients
CNS & Neurological Disorders - Drug Targets Meet Our Editorial Board Member
Mini-Reviews in Medicinal Chemistry Programming Apoptosis and Autophagy with Novel Approaches for Diabetes Mellitus
Current Neurovascular Research Computational Evidence for the Reactivation Process of Human Acetylcholinesterase Inhibited by Carbamates
Combinatorial Chemistry & High Throughput Screening Herbal and Holistic Solutions for Neurodegenerative and Depressive Disorders: Leads from Ayurveda
Current Pharmaceutical Design Ameliorative Potential of Glycyrrhiza glabra Extracts on Memory Impairments in Stress Triggered Rats
Current Traditional Medicine Channel-Like Functions of the 18-kDa Translocator Protein (TSPO): Regulation of Apoptosis and Steroidogenesis as Part of the Host-Defense Response
Current Pharmaceutical Design Vehicles for Lipophilic Drugs: Implications for Experimental Design, Neuroprotection, and Drug Discovery
Current Neurovascular Research Interferon-Related Depression: A Primer on Mechanisms, Treatment, and Prevention of a Common Clinical Problem
Current Neuropharmacology Editorial (Thematic Issue: “Heterocycle and Hydrocarbon Compounds from Natural Sources in Medicinal Chemistry: From Synthesis to Computational Design in Pharmacological Applications” – Part 1)
Current Topics in Medicinal Chemistry Rho Kinase (ROCK) Inhibitors and Their Application to Inflammatory Disorders
Current Topics in Medicinal Chemistry Cerebral Malaria - A Neurovascular Pathology with Many Riddles Still to be Solved
Current Neurovascular Research Current Treatment of Psoriasis with Biologics
Current Drug Discovery Technologies “Letting the Air In” Can Set the Stage for Tumor Recurrences
Current Cancer Therapy Reviews Neurochemistry of the Nucleus Accumbens and its Relevance to Depression and Antidepressant Action in Rodents
Current Neuropharmacology The Effects of Obesity on Drug Metabolism in Children
Drug Metabolism Letters Filtering Disturbances in Schizophrenic Patients. Gating of Auditory Evoked Potentials and Prepulse Inhibition of the Acoustic Startle Response Compared. Emphasis on the Role of Dopamine
Current Neuropharmacology Autism Spectrum Disorders: Role of Pre- and Post-Natal GammaDelta (γδ) T Cells and Immune Regulation
Current Pharmaceutical Design MicroRNA Dysregulation in Alzheimer's Disease
CNS & Neurological Disorders - Drug Targets NMDA Pathology and Treatment of Schizophrenia
Current Pharmaceutical Design