The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Per Artursson - One of the best experts on this subject based on the ideXlab platform.
-
Intracellular Drug Bioavailability : Effect of Neutral Lipids and Phospholipids
Molecular pharmaceutics, 2018Co-Authors: Andrea Treyer, André Mateus, Pär Matsson, Jacek R. Wiśniewski, Hinnerk Boriss, Per ArturssonAbstract:Intracellular unbound Drug concentrations are the pharmacologically relevant concentrations for targets inside cells. Intracellular Drug concentrations are determined by multiple processes, including the extent of Drug binding to intracellular structures. The aim of this study was to evaluate the effect of neutral lipid (NL) and phospholipid (PL) levels on intracellular Drug disposition. The NL and/or PL content of 3T3-L1 cells were enhanced, resulting in phenotypes (in terms of morphology and proteome) reminiscent of adipocytes (high NL and PL) or mild phospholipidosis (only high PL). Intracellular Bioavailability (Fic) was then determined for 23 Drugs in these cellular models and in untreated wild-type cells. A higher PL content led to higher intracellular Drug binding and a lower Fic. The induction of NL did not further increase Drug binding but led to altered Fic due to increased lysosomal pH. Further, there was a good correlation between binding to beads coated with pure PL and intracellular Drug bin...
-
Intracellular Drug Bioavailability: a new predictor of system dependent Drug disposition
Scientific reports, 2017Co-Authors: André Mateus, Andrea Treyer, Christine Wegler, Maria Karlgren, Pär Matsson, Per ArturssonAbstract:Intracellular Drug exposure is influenced by cell- and tissue-dependent expression of Drug-transporting proteins and metabolizing enzymes. Here, we introduce the concept of intracellular Bioavailability (Fic) as the fraction of extracellular Drug available to bind intracellular targets, and we assess how Fic is affected by cellular Drug disposition processes. We first investigated the impact of two essential Drug transporters separately, one influx transporter (OATP1B1; SLCO1B1) and one efflux transporter (P-gp; ABCB1), in cells overexpressing these proteins. We showed that OATP1B1 increased Fic of its substrates, while P-gp decreased Fic. We then investigated the impact of the concerted action of multiple transporters and metabolizing enzymes in freshly-isolated human hepatocytes in culture configurations with different levels of expression and activity of these proteins. We observed that Fic was up to 35-fold lower in the configuration with high expression of Drug-eliminating transporters and enzymes. We conclude that Fic provides a measurement of the net impact of all cellular Drug disposition processes on intracellular bioavailable Drug levels. Importantly, no prior knowledge of the involved Drug distribution pathways is required, allowing for high-throughput determination of Drug access to intracellular targets in highly defined cell systems (e.g., single-transporter transfectants) or in complex ones (including primary human cells).
-
Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability - Drug Bioavailability : estimation of solubility, permeability, absorption and Bioavailability
Methods and Principles in Medicinal Chemistry, 2008Co-Authors: Han Van De Waterbeemd, Hans Lennernäs, Per ArturssonAbstract:Preface.Foreword.List of Authors.I. STUDIES OF MEMBRANE PERMEABILITY AND ORAL ABSORPTION.1. Physico-chemical Approaches to Drug Absorption (H. van de Waterbeemd).2. High-throughput Measurement of log D and pKa (J. Comer).3. High-throughput Measurement of Permeability Profiles (A. Avdeef).4. Caco-2 and Emerging Alternatives for Prediction of Intestinal Drug Transport: A General Overview (P. Artursson & S. Tavelin).5. Cell Cultures in Drug Discovery: An Industrial Perspective (A. Ungell & J. Karlsson).6. Use of Animals for the Determination of Absorption and Bioavailability (C. Logan).7. In Vivo Permeability Studies in the Gastrointestinal Tract of Humans (N. Petri & H. Lennernas).II. Drug DISSOLUTION AND SOLUBILITY.8. Gastrointestinal Dissolution and Absorption of Drugs (G. Granero, et al.).9. Aqueous Solubility in Discovery, Chemistry, and Assay Changes (C. Lipinski).10. Factors Influencing the Water Solubilities of Crystalline Drugs (J. McFarland, et al.).III. ROLE OF TRANSPORTERS AND METABOLISM IN ORAL ABSORPTION.11. Transporters in the GI Tract (H. Shin, et al.).12. Hepatic Transport (H. Suzuki & Y. Sugiyama).13. The Importance of Gut Wall Metabolism in Determining Drug Bioavailability (K. Beaumont).14. Modified Cell Lines (C. Crespi).IV. COMPUTATIONAL APPROACHES TO Drug ABSORPTION AND Bioavailability.15. Intestinal Absorption: The Role of Polar Surface Area (P. Artursson & C. Bergstrom).16. Calculated Molecular Properties and Multivariate Statistical Analysis in Absorption Prediction (U. Norinder & M. Haeberlein).17. VOLSURF: A Tool for Drug ADME-properties Prediction (G. Cruciani, et al.).18. Simulation of Absorption, Metabolism, and Bioavailability (M. Bolger, et al.).19. Prediction of Bioavailability (A. Mandagere & B. Jones).20. Towards P-Glycoprotein Structure-Activity Relationships (A. Seelig, et al.).V. Drug DEVELOPMENT ISSUES.21. Application of the Biopharmaceutical Classification System Now and in the Future (B. Abrahamsson & H. Lennernas).22. ProDrugs (B. Steffansen, et al.).23. Modern Delivery Strategies: Physiological Considerations for Orally Administered Medications (C. Wilson).Index.
-
Drug Bioavailability estimation of solubility permeability absorption and Bioavailability
2003Co-Authors: Han Van De Waterbeemd, Hans Lennernäs, Per ArturssonAbstract:Preface.Foreword.List of Authors.I. STUDIES OF MEMBRANE PERMEABILITY AND ORAL ABSORPTION.1. Physico-chemical Approaches to Drug Absorption (H. van de Waterbeemd).2. High-throughput Measurement of log D and pKa (J. Comer).3. High-throughput Measurement of Permeability Profiles (A. Avdeef).4. Caco-2 and Emerging Alternatives for Prediction of Intestinal Drug Transport: A General Overview (P. Artursson & S. Tavelin).5. Cell Cultures in Drug Discovery: An Industrial Perspective (A. Ungell & J. Karlsson).6. Use of Animals for the Determination of Absorption and Bioavailability (C. Logan).7. In Vivo Permeability Studies in the Gastrointestinal Tract of Humans (N. Petri & H. Lennernas).II. Drug DISSOLUTION AND SOLUBILITY.8. Gastrointestinal Dissolution and Absorption of Drugs (G. Granero, et al.).9. Aqueous Solubility in Discovery, Chemistry, and Assay Changes (C. Lipinski).10. Factors Influencing the Water Solubilities of Crystalline Drugs (J. McFarland, et al.).III. ROLE OF TRANSPORTERS AND METABOLISM IN ORAL ABSORPTION.11. Transporters in the GI Tract (H. Shin, et al.).12. Hepatic Transport (H. Suzuki & Y. Sugiyama).13. The Importance of Gut Wall Metabolism in Determining Drug Bioavailability (K. Beaumont).14. Modified Cell Lines (C. Crespi).IV. COMPUTATIONAL APPROACHES TO Drug ABSORPTION AND Bioavailability.15. Intestinal Absorption: The Role of Polar Surface Area (P. Artursson & C. Bergstrom).16. Calculated Molecular Properties and Multivariate Statistical Analysis in Absorption Prediction (U. Norinder & M. Haeberlein).17. VOLSURF: A Tool for Drug ADME-properties Prediction (G. Cruciani, et al.).18. Simulation of Absorption, Metabolism, and Bioavailability (M. Bolger, et al.).19. Prediction of Bioavailability (A. Mandagere & B. Jones).20. Towards P-Glycoprotein Structure-Activity Relationships (A. Seelig, et al.).V. Drug DEVELOPMENT ISSUES.21. Application of the Biopharmaceutical Classification System Now and in the Future (B. Abrahamsson & H. Lennernas).22. ProDrugs (B. Steffansen, et al.).23. Modern Delivery Strategies: Physiological Considerations for Orally Administered Medications (C. Wilson).Index.
Richard H Guy - One of the best experts on this subject based on the ideXlab platform.
-
In Vivo Methods for the Assessment of Topical Drug Bioavailability
Pharmaceutical Research, 2007Co-Authors: Christophe Herkenne, Ingo Alberti, Aarti Naik, François-xavier Mathy, Véronique Préat, Yogeshvar N. Kalia, Richard H GuyAbstract:This paper reviews some current methods for the in vivo assessment of local cutaneous Bioavailability in humans after topical Drug application. After an introduction discussing the importance of local Drug Bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described.
-
Dermatopharmacokinetic Prediction of Topical Drug Bioavailability In Vivo
The Journal of investigative dermatology, 2006Co-Authors: Christophe Herkenne, Aarti Naik, Yogeshvar N. Kalia, Jonathan Hadgraft, Richard H GuyAbstract:The overall goal of this study was to explore the potential of using stratum corneum (SC) tape-stripping, post-application of a topical Drug formulation, to derive dermatopharmacokinetic parameters describing the rate and extent of delivery into the skin. Ibuprofen was administered in 75:25 v/v propylene glycol-water to the ventral forearms of human volunteers for periods ranging between 15 and 180 minutes. Subsequently, SC was tape-stripped, quantified gravimetrically, and extracted for Drug analysis. Together with concomitant transepidermal water loss measurements, SC concentration-depth profiles of the Drug were reproducibly determined and fitted mathematically. The SC-vehicle partition coefficient (K) and a first-order rate constant related to ibuprofen diffusivity in the membrane (D/L2, where L=SC thickness) were derived from data-fitting and characterized the extent and rate of Drug absorption across the skin. Integration of the concentration profiles yielded the total Drug amount in the SC at the end of the application period. Using K and D/L2 obtained from the 30-minute exposure, it was possible to predict ibuprofen uptake as a function of time into the SC. Prediction and experiment agreed satisfactorily suggesting that objective and quantitative information, with which to characterize topical Drug Bioavailability, can be obtained from this approach.
Christophe Herkenne - One of the best experts on this subject based on the ideXlab platform.
-
In Vivo Methods for the Assessment of Topical Drug Bioavailability
Pharmaceutical Research, 2007Co-Authors: Christophe Herkenne, Ingo Alberti, Aarti Naik, François-xavier Mathy, Véronique Préat, Yogeshvar N. Kalia, Richard H GuyAbstract:This paper reviews some current methods for the in vivo assessment of local cutaneous Bioavailability in humans after topical Drug application. After an introduction discussing the importance of local Drug Bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described.
-
Dermatopharmacokinetic Prediction of Topical Drug Bioavailability In Vivo
The Journal of investigative dermatology, 2006Co-Authors: Christophe Herkenne, Aarti Naik, Yogeshvar N. Kalia, Jonathan Hadgraft, Richard H GuyAbstract:The overall goal of this study was to explore the potential of using stratum corneum (SC) tape-stripping, post-application of a topical Drug formulation, to derive dermatopharmacokinetic parameters describing the rate and extent of delivery into the skin. Ibuprofen was administered in 75:25 v/v propylene glycol-water to the ventral forearms of human volunteers for periods ranging between 15 and 180 minutes. Subsequently, SC was tape-stripped, quantified gravimetrically, and extracted for Drug analysis. Together with concomitant transepidermal water loss measurements, SC concentration-depth profiles of the Drug were reproducibly determined and fitted mathematically. The SC-vehicle partition coefficient (K) and a first-order rate constant related to ibuprofen diffusivity in the membrane (D/L2, where L=SC thickness) were derived from data-fitting and characterized the extent and rate of Drug absorption across the skin. Integration of the concentration profiles yielded the total Drug amount in the SC at the end of the application period. Using K and D/L2 obtained from the 30-minute exposure, it was possible to predict ibuprofen uptake as a function of time into the SC. Prediction and experiment agreed satisfactorily suggesting that objective and quantitative information, with which to characterize topical Drug Bioavailability, can be obtained from this approach.
Pilar Utrilla Navarro - One of the best experts on this subject based on the ideXlab platform.
-
Systematic review of Drug Bioavailability following gastrointestinal surgery
European Journal of Clinical Pharmacology, 2018Co-Authors: M.m. Santamaria, Jimena Abilés, Alberto Fernández López, Lucia Visiedo Rodas, Begoña Tortajada Goitia, Joseph J. Villafranca, Pilar Utrilla NavarroAbstract:PurposeInter- and intraindividual pharmacokinetics variability in humans affects the way in which Drugs act on the body. Gastrointestinal surgery has an impact on this variability and significantly alters the kinetics of Drugs in post-surgical patients. The way in which pharmacokinetic profiles are modified depends on the type of operative procedure performed. The extent to which the absorption of different groups of Drugs is affected varies according to the site and length of intestinal resections.MethodsA literature search was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. Three databases were searched: MEDLINE, Embase, and the Cochrane Library. For each Drug, potential changes in absorption were described, including recommendations extracted from the results of the studies and collected according to authors’ criteria as practical conclusions, and grades of recommendation were determined by levels of evidence using the Oxford Centre for Evidence-Based Medicine scale.ResultsSixty-eight articles were collected during the selection process after the bibliographic search. The main outcomes for 60 Drugs from the various studies were classified according to each type of surgery.ConclusionsModifications in the digestive tract secondary to gastrointestinal surgery may compromise the Bioavailability of Drugs. Decreased absorption surface, gastric emptying speed, and gastric pH alteration are factors to be taken into account in the management of pharmacological treatment after surgery. Evidence supported by data in clinical practice is scarce, but after studying the pharmacokinetic profile of some molecules, it is possible to offer recommendations for its adaptation to the patient’s clinical situation.
-
Systematic review of Drug Bioavailability following gastrointestinal surgery.
European journal of clinical pharmacology, 2018Co-Authors: M.m. Santamaria, Jimena Abilés, Alberto Fernández López, Lucia Visiedo Rodas, Begoña Tortajada Goitia, Joseph J. Villafranca, Pilar Utrilla NavarroAbstract:Inter- and intraindividual pharmacokinetics variability in humans affects the way in which Drugs act on the body. Gastrointestinal surgery has an impact on this variability and significantly alters the kinetics of Drugs in post-surgical patients. The way in which pharmacokinetic profiles are modified depends on the type of operative procedure performed. The extent to which the absorption of different groups of Drugs is affected varies according to the site and length of intestinal resections. A literature search was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. Three databases were searched: MEDLINE, Embase, and the Cochrane Library. For each Drug, potential changes in absorption were described, including recommendations extracted from the results of the studies and collected according to authors’ criteria as practical conclusions, and grades of recommendation were determined by levels of evidence using the Oxford Centre for Evidence-Based Medicine scale. Sixty-eight articles were collected during the selection process after the bibliographic search. The main outcomes for 60 Drugs from the various studies were classified according to each type of surgery. Modifications in the digestive tract secondary to gastrointestinal surgery may compromise the Bioavailability of Drugs. Decreased absorption surface, gastric emptying speed, and gastric pH alteration are factors to be taken into account in the management of pharmacological treatment after surgery. Evidence supported by data in clinical practice is scarce, but after studying the pharmacokinetic profile of some molecules, it is possible to offer recommendations for its adaptation to the patient’s clinical situation.
Adam S Darwich - One of the best experts on this subject based on the ideXlab platform.
-
Physiologically-based pharmacokinetic modelling and simulation of oral Drug Bioavailability : focus on bariatric surgery patients and mechanism-based inhibition of gut wall metabolism
2014Co-Authors: Adam S DarwichAbstract:AbstractTHE UNIVERSITY OF MANCHESTER,Abstract of thesis submitted by Adam S. Darwich, for the degree of PhD and entitled: "Physiologically-based pharmacokinetic modelling and simulation of oral Drug Bioavailability: Focus on bariatric surgery patients and mechanism-based inhibition of gut wall metabolism"Month and year of submission: November 2013.Understanding the processes that govern pre-systemic Drug absorption and elimination is of high importance in pharmaceutical research and development, and clinical pharmacotherapy, as the oral route remains the most frequently used route of Drug administration. The emergence of systems pharmacology has enabled the utilisation of in silico physiologically-based pharmacokinetic (PBPK) modelling and simulation (M&S) coupled to in vitro-in vivo extrapolation in order to perform extrapolation and exploratory M&S in special populations and scenarios were concerns regarding alterations in oral Drug exposure may arise, such as following gastrointestinal (GI) surgery or metabolic Drug-Drug interactions (DDIs).Due to the multi-factorial physiological implications of bariatric surgery, resulting in the partial resection of the GI tract, the inability to rationalise and predict trends in oral Drug Bioavailability (Foral) following surgery present considerable pharmacotherapeutical challenges. PBPK M&S is a highly implemented approach for the prediction of DDIs. Reoccurring issues have emerged with regards to predictions of the magnitude of mechanism-based inhibition (MBI) where overestimations of DDIs have repeatedly been reported for Drugs exhibiting high intestinal extraction.The aim of this thesis was to explore the interplay between oral Drug absorption and metabolism occurring in the GI tract through the exploration of the impact of bariatric surgery on oral Drug exposure and by theoretically examining the nesting and hierarchy of enterocyte and enzyme turnover and its impact on MBIs in the small intestine. This would be carried out by utilising a systems pharmacology PBPK M&S approach under a general model development framework of identification and characterisation of critical intrinsic factors and parameters, model implementation and validation.Developed post bariatric surgery PBPK models allow a framework to theoretically explore physiological mechanisms associated with altered oral Drug exposure pre to post surgery, which could be assigned to the interplay between dissolution, absorption and gut-wall metabolism, where dissolution and formulation properties emerged as the perhaps most important parameters in predicting the Drug disposition following surgery. Model validation identified missing critical factors that are essential for additional model refinement. Developed post bariatric surgery PBPK models have the potential of aiding clinical pharmacotherapy and decision-making following surgery. A mechanistic PBPK model was developed to describe the hierarchical dependency of enzyme and enterocyte turnover in the small intestine. Predicted enzyme recovery using the nested enzyme-within-enterocyte turnover model may potentially account for reported overpredictions of mechanism-based inhibition. Developed models in this thesis showcase the advantage of PBPK M&S in the extrapolation of oral Drug exposure to special population and the potential of a PBPK approach in understanding underlying the underlying mechanism governing Foral and additionally highlight the need for generation of interdisciplinary data to support model development.
-
Evaluation of an In Silico PBPK Post-Bariatric Surgery Model through Simulating Oral Drug Bioavailability of Atorvastatin and Cyclosporine.
CPT: pharmacometrics & systems pharmacology, 2013Co-Authors: Adam S Darwich, Darren M Ashcroft, D Pade, K Rowland-yeo, Masoud Jamei, Asberg A, Hege Christensen, Amin Rostami-hodjeganAbstract:An increasing prevalence of morbid obesity has led to dramatic increases in the number of bariatric surgeries performed. Altered gastrointestinal physiology following surgery can be associated with modified oral Drug Bioavailability (Foral). In the absence of clinical data, an indication of changes to Foral via systems pharmacology models would be of value in adjusting dose levels after surgery. A previously developed virtual “post-bariatric surgery” population was evaluated through mimicking clinical investigations on cyclosporine and atorvastatin after bariatric surgery. Cyclosporine simulations displayed a reduced fraction absorbed through gut wall (fa) and Foral after surgery, consistent with reported observations. Simulated atorvastatin Foral postsurgery was broadly reflective of observed data with indications of counteracting interplay between reduced fa and an increased fraction escaping gut wall metabolism (FG). Inability to fully recover observed atorvastatin exposure after biliopancreatic diversion with duodenal switch highlights the current gap regarding the knowledge of associated biological changes. CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e47; doi:10.1038/psp.2013.23; advance online publication 12 June 2013
-
trends in oral Drug Bioavailability following bariatric surgery examining the variable extent of impact on exposure of different Drug classes
British Journal of Clinical Pharmacology, 2012Co-Authors: Adam S Darwich, Kathryn Henderson, Angela Burgin, Nicola Ward, Janet Whittam, Basil J Ammori, Darren M AshcroftAbstract:UNLABELLED: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ??Changes to oral Drug Bioavailability have been observed post bariatric surgery. However, the magnitude and the direction of changes have not been assessed systematically to provide insights into the parameters governing the observed trends. Understanding these can help with dose adjustments. WHAT THIS STUDY ADDS ??Analysis of Drug characteristics based on a biopharmaceutical classification system is not adequate to explain observed trends in altered oral Drug Bioavailability following bariatric surgery, although the findings suggest solubility to play an important role. AIMS: To identify the most commonly prescribed Drugs in a bariatric surgery population and to assess existing evidence regarding trends in oral Drug Bioavailability post bariatric surgery. METHODS: A retrospective audit was undertaken to document commonly prescribed Drugs amongst patients undergoing bariatric surgery in an NHS hospital in the UK and to assess practice for Drug administration following bariatric surgery. The available literature was examined for trends relating to Drug permeability and solubility with regards to the Biopharmaceutics Classification System (BCS) and main route of elimination. RESULTS: No significant difference in the 'post/pre surgery oral Drug exposure ratio' (ppR) was apparent between BCS class I to IV Drugs, with regards to dose number (Do) or main route of elimination. Drugs classified as 'solubility limited' displayed an overall reduction as compared with 'freely soluble' compounds, as well as an unaltered and increased ppR. CONCLUSION: Clinical studies establishing guidelines for commonly prescribed Drugs, and the monitoring of Drugs exhibiting a narrow therapeutic window or without a readily assessed clinical endpoint, are warranted. Using mechanistically based pharmacokinetic modelling for simulating the multivariate nature of changes in Drug exposure may serve as a useful tool in the further understanding of postoperative trends in oral Drug exposure and in developing practical clinical guidance.
