The Experts below are selected from a list of 279 Experts worldwide ranked by ideXlab platform
L.z. Benet - One of the best experts on this subject based on the ideXlab platform.
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Drug Classification and Drug Disposition Prediction
Comprehensive Medicinal Chemistry III, 2017Co-Authors: C.m. Hosey, L.z. BenetAbstract:A Drug’s Disposition depends upon the processes of absorption from a dosing site, distribution to target and other peripheral and systemic tissues, and elimination by either metabolism or excretion of unchanged Drug. These processes interact to characterize Drugs by their pharmacokinetic profile as observed in a plasma concentration–time curve. The pharmacokinetic profile and alterations of this profile can impact the safety and efficacy of a Drug. Pharmaceutical scientists have therefore developed methods to predict absorption, distribution, metabolism, and excretion of unchanged Drug as well as understand when each of these processes may be altered and by what mechanisms. In this article, we discuss our current understanding and challenges in predicting these processes. We focus on the Biopharmaceutics Classification System (BCS) and the Biopharmaceutics Drug Disposition Classification System (BDDCS). The BCS, developed by Amidon and coworkers in 1995, is used primarily to understand absorption and grant biowaivers to Drugs using permeability and solubility parameters. The BDDCS, developed by Wu and Benet in 2005, is used to qualitatively predict Drug Disposition and understand whether metabolizing enzymes and/or transporters will impact Drug Disposition. Here, we discuss the rationale, development, classification, predictive utilities, limitations, and possibilities of these approaches.
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Predicting Drug Disposition via Application of a Biopharmaceutics Drug Disposition Classification System
Basic & clinical pharmacology & toxicology, 2009Co-Authors: L.z. BenetAbstract:A Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters in determining Drug bioavailability and Disposition. BDDCS may be useful in predicting: routes of Drug elimination; efflux and absorptive transporters effects on oral absorption; when transporter-enzyme interplay will yield clinically significant effects (e.g. low Drug bioavailability and Drug-Drug interactions); and transporter effects on post-absorptive systemic Drug levels following oral and i.v. dosing. For highly soluble, highly permeable Class 1 compounds, metabolism is the major route of elimination and transporter effects on Drug bioavailability and hepatic Disposition are negligible. In contrast for the poorly permeable Class 3 and 4 compounds, metabolism only plays a minor role in Drug elimination. Uptake transporters are major determinants of Drug bioavailability for these poorly permeable Drugs and both uptake and efflux transporters could be important for Drug elimination. Highly permeable, poorly soluble, extensively metabolized Class 2 compounds present the most complicated relationship in defining the impact of transporters due to a marked transporter-enzyme interplay. Uptake transporters are unimportant for Class 2 Drug bioavailability, (ensure space after,) but can play a major role in hepatic and renal elimination. Efflux transporters have major effects on Drug bioavailability, absorption, metabolism and elimination of Class 2 Drugs. It is difficult to accurately characterize Drugs in terms of the high permeability criteria, i.e. > or =90% absorbed. We suggest that extensive metabolism may substitute for the high permeability characteristic, and that BDDCS using elimination criteria may provide predictability in characterizing Drug Disposition profiles for all classes of compounds.
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Predicting Drug Disposition via Application of BCS: Transport/Absorption/ Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System
Pharmaceutical Research, 2005Co-Authors: L.z. BenetAbstract:The Biopharmaceutics Classification System (BCS) was developed to allow prediction of in vivo pharmacokinetic performance of Drug products from measurements of permeability (determined as the extent of oral absorption) and solubility. Here, we suggest that a modified version of such a classification system may be useful in predicting overall Drug Disposition, including routes of Drug elimination and the effects of efflux and absorptive transporters on oral Drug absorption; when transporter-enzyme interplay will yield clinically significant effects (e.g., low bioavailability and Drug-Drug interactions); the direction, mechanism, and importance of food effects; and transporter effects on postabsorption systemic Drug concentrations following oral and intravenous dosing. These predictions are supported by a series of studies from our laboratory during the past few years investigating the effect of transporter inhibition and induction on Drug metabolism. We conclude by suggesting that a Biopharmaceutics Drug Disposition Classification System (BDDCS) using elimination criteria may expand the number of Class 1 Drugs eligible for a waiver of in vivo bioequivalence studies and provide predictability of Drug Disposition profiles for Classes 2, 3, and 4 compounds.
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Predicting Drug Disposition via Application of BCS: Transport/Absorption/ Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System
Pharmaceutical research, 2005Co-Authors: L.z. BenetAbstract:The Biopharmaceutics Classification System (BCS) was developed to allow prediction of in vivo pharmacokinetic performance of Drug products from measurements of permeability (determined as the extent of oral absorption) and solubility. Here, we suggest that a modified version of such a classification system may be useful in predicting overall Drug Disposition, including routes of Drug elimination and the effects of efflux and absorptive transporters on oral Drug absorption; when transporter-enzyme interplay will yield clinically significant effects (e.g., low bioavailability and Drug-Drug interactions); the direction, mechanism, and importance of food effects; and transporter effects on postabsorption systemic Drug concentrations following oral and intravenous dosing. These predictions are supported by a series of studies from our laboratory during the past few years investigating the effect of transporter inhibition and induction on Drug metabolism. We conclude by suggesting that a Biopharmaceutics Drug Disposition Classification System (BDDCS) using elimination criteria may expand the number of Class 1 Drugs eligible for a waiver of in vivo bioequivalence studies and provide predictability of Drug Disposition profiles for Classes 2, 3, and 4 compounds.
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predicting Drug Disposition via application of bcs transport absorption elimination interplay and development of a biopharmaceutics Drug Disposition classification system
Pharmaceutical Research, 2005Co-Authors: L.z. BenetAbstract:The Biopharmaceutics Classification System (BCS) was developed to allow prediction of in vivo pharmacokinetic performance of Drug products from measurements of permeability (determined as the extent of oral absorption) and solubility. Here, we suggest that a modified version of such a classification system may be useful in predicting overall Drug Disposition, including routes of Drug elimination and the effects of efflux and absorptive transporters on oral Drug absorption; when transporter-enzyme interplay will yield clinically significant effects (e.g., low bioavailability and Drug-Drug interactions); the direction, mechanism, and importance of food effects; and transporter effects on postabsorption systemic Drug concentrations following oral and intravenous dosing. These predictions are supported by a series of studies from our laboratory during the past few years investigating the effect of transporter inhibition and induction on Drug metabolism. We conclude by suggesting that a Biopharmaceutics Drug Disposition Classification System (BDDCS) using elimination criteria may expand the number of Class 1 Drugs eligible for a waiver of in vivo bioequivalence studies and provide predictability of Drug Disposition profiles for Classes 2, 3, and 4 compounds.
Leonardo Sahelijo - One of the best experts on this subject based on the ideXlab platform.
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Defining Drug Disposition determinants: a pharmacogenetic–pharmacokinetic strategy
Nature Reviews Drug Discovery, 2008Co-Authors: David A. Katz, Bernard Murray, Anahita Bhathena, Leonardo SahelijoAbstract:In preclinical and early clinical Drug development, information about the factors influencing Drug Disposition is used to predict Drug interaction potential, estimate and understand population pharmacokinetic variability, and select doses for clinical trials. However, both in vitro Drug metabolism studies and pharmacogenetic association studies on human pharmacokinetic parameters have focused on a limited subset of the proteins involved in Drug Disposition. Furthermore, there has been a one-way information flow, solely using results of in vitro studies to select candidate genes for pharmacogenetic studies. Here, we propose a two-way pharmacogenetic–pharmacokinetic strategy that exploits the dramatic recent expansion in knowledge of functional genetic variation in proteins that influence Drug Disposition, and discuss how it could improve Drug development. Katz and colleagues summarize knowledge on associations between Drug pharmacokinetics and variations in genes coding for proteins involved in Drug Disposition. They propose a novel strategy in which pharmacogenetic data from early clinical studies is used both to feed back to further in vitro studies of Drug pharmacokinetics and to feed forward to optimize later-stage clinical trials, and discuss how this could improve Drug development.
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Defining Drug Disposition determinants: a pharmacogenetic–pharmacokinetic strategy
Nature reviews. Drug discovery, 2008Co-Authors: David A. Katz, Anahita Bhathena, Bernard P. Murray, Leonardo SahelijoAbstract:Katz and colleagues summarize knowledge on associations between Drug pharmacokinetics and variations in genes coding for proteins involved in Drug Disposition. They propose a novel strategy in which pharmacogenetic data from early clinical studies is used both to feed back to further in vitro studies of Drug pharmacokinetics and to feed forward to optimize later-stage clinical trials, and discuss how this could improve Drug development.
Michael S. Roberts - One of the best experts on this subject based on the ideXlab platform.
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The development of models for the evaluation of pulmonary Drug Disposition.
Expert opinion on drug metabolism & toxicology, 2013Co-Authors: Xin Liu, Lu Jin, John W. Upham, Michael S. RobertsAbstract:Introduction: The process of Drug Disposition in the lung after pulmonary delivery is complex involving absorptive and non-absorptive mechanisms. The lung has also been suggested to be a trapping and metabolizing organ, especially after intravenous administration of Drug. A key challenge is to define the most suitable models for the evaluation of pulmonary Drug Disposition. Areas covered: This review provides an overview of the anatomy and physiology of the lung and sites of action. The authors follow this with a description of the processes associated with pulmonary Disposition (deposition, absorption, distribution, metabolism, and non-absorptive clearance). The article also summarizes and compares models and techniques for the assessment of Drug Disposition in the lung, in terms of characteristic features, advantages and disadvantages. Finally, the authors review pharmaceutical science implications of these findings. Expert opinion: In vivo models are preferred for studying Drug deposition, absorption, ...
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Liver Transporters in Hepatic Drug Disposition: An Update
Current drug metabolism, 2009Co-Authors: Guangji Wang, Thomas Robertson, Michael S. RobertsAbstract:Drug transporters expressed on the hepatocyte membrane play an important role in hepatic Drug Disposition. In the last two decades, systematic research has resulted in a better understanding of the diversity, expression and substrate specificities of Drug transporters in the liver. Here we review recent studies on the role of transporters in Drug-Drug interactions and disease states such as cirrhosis. We conclude the review by considering techniques and model systems used to study hepatic transporters, including the latest technological developments such as multiphoton microscopy.
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Computational Strategies Unravel and Trace How Liver Disease Changes Hepatic Drug Disposition
The Journal of pharmacology and experimental therapeutics, 2008Co-Authors: Sunwoo Park, Michael S. Roberts, Glen E. P. Ropella, Sean H. J. Kim, C. Anthony HuntAbstract:Liver disease changes the Disposition properties of Drugs, complicating Drug therapy management. We present normal and “diseased” versions of an abstract, agent-oriented In Silico Livers (ISLs), and validate their mechanisms against Disposition data from perfused normal and diseased rat livers. Dynamic tracing features enabled spatiotemporal tracing of differences in Dispositional events for diltiazem and sucrose across five levels, including interactions with representations of lobular microarchitectural features, cells, and intracellular factors that sequester and metabolize. Differences in attributes map to measures of histopathology. We measured disease-causing differences in local, intralobular ISL effects, obtaining until now unavailable views of how and where hepatic Drug Disposition may differ in normal and diseased rat livers from diltiazem's perspective. Exploration of Disposition in less and more advanced stages of disease is feasible. The approach and technology represent an important step toward unraveling the complex changes from normal to disease states and their influences on Drug Disposition.
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EFFECTS OF HYPOXIA/REPERFUSION INJURY ON Drug Disposition IN THE RAT ISOLATED PERFUSED LIVER
Clinical and experimental pharmacology & physiology, 2007Co-Authors: H A Arab, Kee Cheung, Peter E. Hickman, Julia M. Potter, Mehri Kadkhodaee, Michael S. RobertsAbstract:1. Ischaemia-reperfusion injury is known to be associated with a range of functional and structural alterations in the liver. However, the effect of this injury on Drug Disposition is not well understood. The present study was designed to examine the effects of hypoxia/reperfusion on the Disposition of glutamate and propranolol in the rat isolated perfused liver. Both glutamate and propranolol are mainly metabolised in the pericentral region of the liver.
David A. Katz - One of the best experts on this subject based on the ideXlab platform.
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Encyclopedia of Drug Metabolism and Interactions - Genetics of Drug Disposition
Encyclopedia of Drug Metabolism and Interactions, 2012Co-Authors: Anahita Bhathena, David A. KatzAbstract:Drug Disposition, a complex process culminating from the interplay of numerous Drug–metabolizing enzymes, Drug transport proteins, serum-binding proteins, and transcription factors, is affected by multiple environmental and endogenous factors. Genetic variations in Drug–metabolizing enzymes and Drug transport proteins contribute toward variability in Drug Disposition. Our knowledge of these functional genetic variants and the tools to interrogate them are well developed. These tools have found use in Drug development within the pharmaceutical industry, and for limited applications, making clinical treatment decisions. This chapter discusses the genetic variations in Drug–metabolizing enzymes and transporters and their relevance for clinical pharmacokinetics. Keywords: pharmacogenetics; Drug metabolism; polymorphism; Drug transport; Drug Disposition
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Defining Drug Disposition determinants: a pharmacogenetic–pharmacokinetic strategy
Nature Reviews Drug Discovery, 2008Co-Authors: David A. Katz, Bernard Murray, Anahita Bhathena, Leonardo SahelijoAbstract:In preclinical and early clinical Drug development, information about the factors influencing Drug Disposition is used to predict Drug interaction potential, estimate and understand population pharmacokinetic variability, and select doses for clinical trials. However, both in vitro Drug metabolism studies and pharmacogenetic association studies on human pharmacokinetic parameters have focused on a limited subset of the proteins involved in Drug Disposition. Furthermore, there has been a one-way information flow, solely using results of in vitro studies to select candidate genes for pharmacogenetic studies. Here, we propose a two-way pharmacogenetic–pharmacokinetic strategy that exploits the dramatic recent expansion in knowledge of functional genetic variation in proteins that influence Drug Disposition, and discuss how it could improve Drug development. Katz and colleagues summarize knowledge on associations between Drug pharmacokinetics and variations in genes coding for proteins involved in Drug Disposition. They propose a novel strategy in which pharmacogenetic data from early clinical studies is used both to feed back to further in vitro studies of Drug pharmacokinetics and to feed forward to optimize later-stage clinical trials, and discuss how this could improve Drug development.
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Defining Drug Disposition determinants: a pharmacogenetic–pharmacokinetic strategy
Nature reviews. Drug discovery, 2008Co-Authors: David A. Katz, Anahita Bhathena, Bernard P. Murray, Leonardo SahelijoAbstract:Katz and colleagues summarize knowledge on associations between Drug pharmacokinetics and variations in genes coding for proteins involved in Drug Disposition. They propose a novel strategy in which pharmacogenetic data from early clinical studies is used both to feed back to further in vitro studies of Drug pharmacokinetics and to feed forward to optimize later-stage clinical trials, and discuss how this could improve Drug development.
Henk-jan Guchelaar - One of the best experts on this subject based on the ideXlab platform.
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Breath Tests to Phenotype Drug Disposition in Oncology
Clinical Pharmacokinetics, 2013Co-Authors: Frans L. Opdam, Hans Gelderblom, Anil S. Modak, Henk-jan GuchelaarAbstract:Breath tests (BTs) have been investigated as diagnostic tools to phenotype Drug Disposition in cancer patients in the pursuit to individualize Drug treatment. The choice of the right phenotype probe is crucial and depends on the metabolic pathway of the anticancer agent of interest. BTs using orally or intravenously administered selective non-radioactive ^13C-labeled probes to non-invasively evaluate dihydropyrimidine dehydrogenase, cytochrome P450 (CYP) 3A4, and CYP2D6 enzyme activity have been published. Clinically, a ^13C-dextromethorphan BT to predict endoxifen levels in breast cancer patients and a ^13C-uracil BT to predict fluoropyrimidine toxicity in colorectal cancer patients are most promising. However, the clinical benefit and cost effectiveness of these phenotype BTs need to be determined in order to make the transition from an experimental setting to clinical practice as companion diagnostic tests.
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Phenotyping Drug Disposition in oncology
Cancer treatment reviews, 2012Co-Authors: Frans L. Opdam, Hans Gelderblom, Henk-jan GuchelaarAbstract:Efficacy and toxicity of anticancer agents are highly variable between patients and variation in Drug Disposition is thought to be an important determinant. Genetics, physiology, and environment all are underlying factors contributing to this variation. Phenotyping Drug metabolizing enzymes and Drug transporters by using in vivo probes is a method that can be used to individualize Drug therapy. This review discusses Drug Disposition of anticancer agents and the potential of phenotyping probes for phase I, II metabolic enzymes, and Drug transporters in oncology.
