A5071065147- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Advanced Proteomics Techniques and Applications
- Metabolomics and Mass Spectrometry Studies
- Mass Spectrometry Techniques and Applications
- Pharmacological Effects and Toxicity Studies
- Blood groups and transfusion
- Statistical Methods in Clinical Trials
- Amino Acid Enzymes and Metabolism
- Liver Disease Diagnosis and Treatment
- Analytical Chemistry and Chromatography
- Glycosylation and Glycoproteins Research
- Computational Drug Discovery Methods
- Erythrocyte Function and Pathophysiology
- Drug-Induced Hepatotoxicity and Protection
- Chronic Lymphocytic Leukemia Research
- Metabolism and Genetic Disorders
- Viral-associated cancers and disorders
- Receptor Mechanisms and Signaling
- Blood disorders and treatments
- Immunodeficiency and Autoimmune Disorders
- Bacterial Identification and Susceptibility Testing
- Biochemical and Molecular Research
- Complement system in diseases
- Advanced Biosensing Techniques and Applications
University of Manchester
2015-2025
University of Rhode Island
2022-2025
Manchester Academic Health Science Centre
2022-2025
Hôpital Farhat Hached
2012-2021
Merck (Germany)
2021
Certara (United States)
2014-2021
Simcyp (United Kingdom)
2014-2021
Tanta University
2020-2021
University of Sousse
2020
Wellcome Centre for Cell-Matrix Research
2020
Cytochrome P450 (P450) and uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes mediate a major proportion of phase I II metabolism xenobiotics. In vitro-in vivo extrapolation (IVIVE) hepatic clearance in conjunction with physiologically-based pharmacokinetics (PBPK) has become common practice drug development. However, prediction xenobiotic kinetics virtual populations requires knowledge both enzyme abundances the extent to which these correlate. A multiplexed quantification...
Many different methods are used for mass-spectrometry-based protein quantification in pharmacokinetics and systems pharmacology. It has not been established to what extent the results from these various comparable. Here, we compared six mass spectrometry-based proteomics by measuring expression of clinically relevant drug transporters metabolizing enzymes human liver. Mean concentrations were general quantified similar levels using whole tissue lysates. Methods subcellular membrane...
The blood-brain barrier (BBB) maintains brain homeostasis by controlling traffic of molecules from the circulation into brain. This function is predominantly dependent on proteins expressed at BBB, especially transporters and tight junction proteins. Alterations to level BBB can impact susceptibility central nervous system exposure xenobiotics in systemic with potential consequent effects function. In this study, expression profiles drug solute carriers were assessed tissues healthy...
Quantitative translation of information on drug absorption, disposition, receptor engagement, and drug–drug interactions from bench to bedside requires models informed by physiological parameters that link in vitro studies vivo outcomes. To predict outcomes, biochemical data experimental systems are routinely scaled using protein quantity these relevant tissues. Although several laboratories have generated useful quantitative proteomic state‐of‐the‐art mass spectrometry, no harmonized...
The levels of drug-metabolizing enzymes (DMEs) and transporter proteins in the human intestine are pertinent to determine oral drug bioavailability. Despite paucity reports on such measurements, it is well recognized that these values essential for translating vitro data metabolism transport predict disposition gut wall. In current study, clinically relevant DMEs [cytochrome P450 (P450) uridine 5′-diphospho-glucuronosyltransferase (UGT)] transporters were quantified total mucosal protein...
The cytochrome P450 (P450) family of enzymes is a major player in the metabolism therapeutic drugs available on market, and development novel has to take into account these fate new drugs. Testing pharmacokinetic behavior animals common part drug process. Pigs are increasingly used for this purpose because their similarity enzymatic pattern humans. In study, adult Suffolk White pig liver microsomal samples were analyzed using mass-spectrometry-based techniques identify relatively quantify...
There is an urgent need (recognized in FDA guidance, 2018) to optimize the dose of medicines given patients for maximal drug efficacy and limited toxicity (precision dosing), which can be facilitated by quantitative systems pharmacology (QSP) models. Accurate quantification proteins involved clearance essential build improve QSP models any target population. Here we describe application label-free proteomics microsomes from 23 human livers simultaneously quantify 188 enzymes 66 transporters...
Variability in individual capacity for hepatic elimination of therapeutic drugs is well recognized and associated with variable expression activity liver enzymes transporters. Although genotyping offers some degree stratification, there often large variability within the same genotype. Direct measurement protein impractical due to limited access tissue biopsies. Hence, determination drug metabolism disposition using liquid biopsy (blood samples) an attractive proposition during development...
Abstract The blood–brain barrier ( BBB ) maintains brain homeostasis by tightly regulating the exchange of molecules with systemic circulation. It consists primarily microvascular endothelial cells surrounded astrocytic endfeet, pericytes, and microglia. Understanding make‐up transporters in rat is essential to translation pharmacological toxicological observations into humans. In this study, experimental workflows are presented which optimization (a) isolation microvessels (b) enrichment...
Liver cirrhosis is a chronic disease that affects the liver structure, protein expression, and overall metabolic function. Abundance data for drug-metabolizing enzymes transporters (DMET) across all stages of severity are scarce. Levels these proteins crucial accurate prediction drug clearance in hepatically impaired patients using physiologically based pharmacokinetic (PBPK) models, which can be used to guide selection more precise dosing. This study aimed experimentally quantify human...
Precision dosing strategies require accounting for between-patient variability in pharmacokinetics together with subsequent pharmacodynamic differences. Liquid biopsy is a valuable new approach to diagnose disease prior the appearance of clinical signs and symptoms, potentially circumventing invasive tissue biopsies. However, possibility quantitative grading biomarkers, as opposed simply confirming their presence or absence, relatively new. In this study, we aimed verify expression...
Transporter proteins expressed in the gastrointestinal tract play a major role oral absorption of some drugs, and their involvement may lead to drug-drug interaction (DDI) susceptibility when given combination with drugs known inhibit gut wall transporters. Anticipating such liabilities predicting magnitude impact transporter on drug DDIs requires quantification expression human intestine, linking these data obtained through vitro experiments. A quantitative targeted absolute proteomic...
QconCAT is a tool for quantitative proteomics, consisting of an artificial protein, expressed from gene, made up concatenated string proteotypic peptides selected the proteins under study. Isotopically labeled (usually containing 13C6-arginine and 13C6-lysine) provides standard each peptide included in its sequence. In practice, some fail to express at sufficient levels purpose analysis. Two complementary methods are presented recalcitrant intended quantify human hepatic enzymes transporters.
Over the last 5 years quantification of transporter-protein absolute abundances has dramatically increased in parallel to expanded use vitro–in vivo extrapolation (IVIVE) and physiologically based pharmacokinetics (PBPK)-linked models, for decision-making pharmaceutical company drug development pipelines regulatory submissions. Although several research groups have developed laboratory-specific proteomic workflows, it is unclear if large range reported variability founded on true...
Precision dosing strategies require accounting for between-patient variability in pharmacokinetics (PK), affecting drug exposure, and pharmacodynamics (PD), response achieved at the same concentration site of action. Although liquid biopsy assessing different levels molecular targets has yet to be established, individual characterization elimination pathways using recently been demonstrated. The feasibility applying this approach conjunction with modeling tools guide remains unexplored. In...
Abstract Background Carbapenem-resistant Enterobacterales (CRE) are an urgent threat. We modeled epithelial lining fluid (ELF) and serum concentrations of meropenem (MER), meropenem-vaborbactam (MV), ceftazidime-avibactam (CA) to assist in treatment selection. Meropenem, meropenem-vaborbactam, dosing simulating ELF with a non-CP-producing CRE Methods Two E. cloacae were evaluated, one non-carbapenemase (CP) producing isolate multiple porin mutations blaACT-15, blaKPC-3 CP-producing isolate....
The aim of study was to generate quantitative data on the abundance drug-metabolizing enzymes and transporters (DMETs) in inflamed non-inflamed Crohn's disease (CD) ileum colon, for incorporation into physiologically based pharmacokinetic (PBPK) models, enabling prediction oral drugs' pharmacokinetics (PK) perturbation CD patients. Homogenate fractions were processed from 13 (six seven colon) (two five 10 healthy (five tissues deceased subjects by calcium chelation elution, protein...
Many genetic and environmental factors lead to interindividual variations in the metabolism transport of drugs, profoundly affecting efficacy toxicity. Precision dosing, that is, targeting drug dose a well characterized subpopulation, is dependent on quantitative models profiles drug-metabolizing enzymes (DMEs) transporters within informed by proteomics. We report first use ion mobility–mass spectrometry for this purpose, allowing rapid, robust, label-free quantification human liver...