Abstract
The use of in vitro metabolism in scaling to predict human clearance of new chemical entities has become a commonplace activity in the research and development of new drugs. The measurement of in vitro lability in human liver microsomes, a rich source of drug metabolizing cytochrome P450 enzymes, has become a high throughput screen in many research organizations which is a testament to its usefulness in drug design. In this chapter, the methods used to scale in vitro intrinsic clearance data to predict in vivo clearance are described. Importantly, the numerous assumptions that are required in order to use in vitro data in this manner are laid out. These include assumptions regarding the scaling process as well as technical aspects of the generation of the in vitro data. Finally, some other drug clearance processes that have been emerging as important are described with regard to ongoing research efforts to develop clearance prediction methods.
Keywords: Clearance, intrinsic clearance, liver microsomes, cytochrome P450, glucuronidation, aldehyde oxidase, drug transporters
Current Topics in Medicinal Chemistry
Title: Predicting Clearance in Humans from In Vitro Data
Volume: 11 Issue: 4
Author(s): R. Scott Obach
Affiliation:
Keywords: Clearance, intrinsic clearance, liver microsomes, cytochrome P450, glucuronidation, aldehyde oxidase, drug transporters
Abstract: The use of in vitro metabolism in scaling to predict human clearance of new chemical entities has become a commonplace activity in the research and development of new drugs. The measurement of in vitro lability in human liver microsomes, a rich source of drug metabolizing cytochrome P450 enzymes, has become a high throughput screen in many research organizations which is a testament to its usefulness in drug design. In this chapter, the methods used to scale in vitro intrinsic clearance data to predict in vivo clearance are described. Importantly, the numerous assumptions that are required in order to use in vitro data in this manner are laid out. These include assumptions regarding the scaling process as well as technical aspects of the generation of the in vitro data. Finally, some other drug clearance processes that have been emerging as important are described with regard to ongoing research efforts to develop clearance prediction methods.
Export Options
About this article
Cite this article as:
Scott Obach R., Predicting Clearance in Humans from In Vitro Data, Current Topics in Medicinal Chemistry 2011; 11 (4) . https://dx.doi.org/10.2174/156802611794480873
DOI https://dx.doi.org/10.2174/156802611794480873 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Medicinal Chemistry Advancement in Life-Threatening Diseases
The current issue will highlight concise reports that specify ground-breaking insights, including the novel discovery of drug targets and their action mechanism or drugs of novel classes. These are projected to encourage medicinal chemistry future efforts to address the most challenging medical needs. The current issue highlights further efforts to ...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
-
From Amino Acids to Proteins as Targets for Metal-based Drugs
Current Drug Metabolism Addressing the Challenge: Current and Future Directions in Ovarian Cancer Therapy
Current Gene Therapy Changing Faces of Transcriptional Regulation Reflected by Zic3
Current Genomics Review and Research on Feature Selection Methods from NMR Data in Biological Fluids. Presentation of an Original Ensemble Method Applied to Atherosclerosis Field
Current Drug Metabolism Opto-Acoustic Imaging of Drug Discovery Biomarkers
Current Pharmaceutical Biotechnology Global Cell Proteome Profiling, Phospho-signaling and Quantitative Proteomics for Identification of New Biomarkers in Acute Myeloid Leukemia Patients
Current Pharmaceutical Biotechnology Detoxification of Aflatoxin M1 (AFM1) in Dairy Base Beverages (Acidophilus Milk) by Using Different Types of Lactic Acid Bacteria-Mini Review
Current Nutrition & Food Science Assembled Core-Shell Nanostructures of Gold Nanoparticles with Biocompatible Polymers Toward Biology
Current Topics in Medicinal Chemistry Recent Developments in Polymeric Nanoparticle Engineering and Their Applications in Experimental and Clinical Oncology
Anti-Cancer Agents in Medicinal Chemistry Yeast Genomics and Drug Target Identification
Combinatorial Chemistry & High Throughput Screening Metabolism of Dietary Flavonoids in Liver Microsomes
Current Drug Metabolism A Review on Differential Isotope-coded Derivatization Reagents for LC-API-MS Analyses
Current Analytical Chemistry Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition
Current Medicinal Chemistry Preparation and Evaluation of Lysozyme Molecularly Imprinted Polymer Film on the Surface of Multi-wall Carbon Nanotubes
Current Organic Chemistry Synthesis and Study of the Antimicrobial Activity of Novel Tricyclic 2 Hpyrimido [2,1-b]benzothiazoles
Letters in Drug Design & Discovery Quantitative Estimation of Lead (Pb) and Cadmium (Cd) Content in Commonly Used Cosmeceuticals Using Atomic Absorption Spectroscopy
Current Pharmaceutical Analysis Recent Advances in Solid-Phase Microextraction and Related Techniques for Pharmaceutical and Biomedical Analysis
Current Pharmaceutical Analysis The Molecular Targets of Cannabinoids in the Treatment of Cancer and Inflammation
Current Pharmaceutical Design Pyrimidine-fused Dinitrogenous Penta-heterocycles as a Privileged Scaffold for Anti-Cancer Drug Discovery
Current Topics in Medicinal Chemistry Seeing the Light: Luminescent Reporter Gene Assays
Combinatorial Chemistry & High Throughput Screening