A5059236152- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Pharmacological Effects and Toxicity Studies
- Computational Drug Discovery Methods
- Liver Disease Diagnosis and Treatment
- Analytical Methods in Pharmaceuticals
- Analytical Chemistry and Chromatography
- Drug-Induced Hepatotoxicity and Protection
- Diet and metabolism studies
- Renal Transplantation Outcomes and Treatments
- Metabolism and Genetic Disorders
- Receptor Mechanisms and Signaling
- Drug Solubulity and Delivery Systems
- Pharmaceutical studies and practices
- HIV/AIDS drug development and treatment
- Chronic Kidney Disease and Diabetes
- Antibiotics Pharmacokinetics and Efficacy
- Diabetes Treatment and Management
- Metabolomics and Mass Spectrometry Studies
- Statistical Methods in Clinical Trials
- 3D Printing in Biomedical Research
- Lipoproteins and Cardiovascular Health
- Inhalation and Respiratory Drug Delivery
- Calcium signaling and nucleotide metabolism
- Amino Acid Enzymes and Metabolism
University of Manchester
2016-2025
Manchester Academic Health Science Centre
2019-2025
University of New Hampshire at Manchester
2019
Eli Lilly (United States)
2013-2018
Simcyp (United Kingdom)
2017-2018
UCB Pharma (United Kingdom)
2018
Pfizer (United States)
2015-2018
Ono Pharmaceutical (Japan)
2018
Certara (United States)
2018
Shionogi (Japan)
2018
Intestinal first-pass metabolism may contribute to low oral drug bioavailability and drug-drug interactions, particularly for CYP3A substrates. The current analysis predicted intestinal availability (<i>F</i><sub>G</sub>) from in vitro metabolic clearance permeability data of 25 drugs using the <i>Q</i><sub>Gut</sub> model. selection included a wide range physicochemical properties vivo <i>F</i><sub>G</sub> values (0.07–0.94). In (CLu<sub>int</sub>) were determined human (HIM) three liver...
With efforts to reduce cytochrome P450-mediated clearance (CL) during the early stages of drug discovery, transporter-mediated CL mechanisms are becoming more prevalent. However, prediction plasma concentration-time profiles for such compounds using physiologically based pharmacokinetic (PBPK) modeling is far less established in comparison with that passively mediated pharmacokinetics (PK). In this study, we have assessed predictability human PK seven organic anion-transporting polypeptide...
The glucuronidation kinetics of the prototypic substrates 4-methylumbelliferone (4MU) and 1-naphthol (1NP) by human UDP-glucuronosyltransferases (UGT) 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, 2B17 were investigated. Where activity was demonstrated, inhibitory effects diclofenac, probenecid, solvents acetone, acetonitrile, dimethyl sulfoxide, ethanol, methanol characterized. All isoforms except UGT1A4 glucuronidated 4MU, whereas all but UGT metabolized 1NP. However, kinetic models...
Morphine elimination involves UDP-glucuronosyltransferase (UGT) catalyzed conjugation with glucuronic acid to form morphine 3- and 6-glucuronides (M3G M6G, respectively). It has been proposed that UGT2B7 is the major enzyme involved in these reactions, but there evidence suggest other isoforms also catalyze glucuronidation man. Thus, we have characterized selectivity kinetics of M3G M6G formation by recombinant human UGTs. UGT 1A1, 1A3, 1A6, 1A8, 1A9, 1A10, 2B7 all formation, only formed...
Glucuronidation via UDP-glucuronosyltransferase (UGT) is an increasingly important clearance pathway. In this study intrinsic (CL<sub>int</sub>) values for buprenorphine, carvedilol, codeine, diclofenac, gemfibrozil, ketoprofen, midazolam, naloxone, raloxifene, and zidovudine were determined in pooled human liver microsomes using the substrate depletion approach. The vitro data indicated a varying contribution of glucuronidation to compounds studied, ranging from 6 79% midazolam...
Current assessment of drug-drug interaction (DDI) prediction success is based on whether predictions fall within a two-fold range the observed data. This strategy results in potential bias toward successful at lower levels [ratio area under concentration-time profile (AUC) presence inhibitor/inducer compared with control <2]. scenario can any different DDI algorithms if databases contain large proportion interactions this range. Therefore, current study proposes an alternative method to...
Analogous to the fraction unbound in microsomes (fu<sub>mic</sub>), hepatocyte incubations (fu<sub>hep</sub>) is an important parameter prediction of intrinsic clearance and potential drug-drug interactions. A recent study by Austin et al. (<i>Drug Metab Dispos</i> 33:419–425, 2005) proposed a linear 1:1 relationship between extent binding at 1 mg/ml hepatocytes 10<sup>6</sup> million cells/ml. The current collates fu<sub>mic</sub> fu<sub>hep</sub> database for 39 drugs examine hepatocytes....
Prediction of intestinal availability (<i>F</i><sub>G</sub>), in conjunction with hepatic metabolism, is considerable importance drug disposition to assess oral clearance and liability drug-drug interactions. In the current study, <i>F</i><sub>G</sub> predictions were performed within a physiologically based pharmacokinetic (PBPK) model using vitro permeability data. The prediction success was assessed comparison <i>Q</i><sub>Gut</sub> model. addition, apparent values, predicted PBPK model,...
To explore the determinants of hepatic uptake, 16 compounds were investigated with different physicochemical and disposition characteristics, including five statins, three sartans, saquinavir, ritonavir, erythromycin, clarithromycin, nateglinide, repaglinide, fexofenadine, bosentan. Freshly isolated rat hepatocytes in suspension used oil-spin method to generate kinetic parameters. Clearances, via passive diffusion (<i>P</i><sub>diff</sub>) active uptake (CL<sub>active</sub>, characterized by...
The current study assesses hepatic and intestinal glucuronidation, sulfation, cytochrome P450 (P450) metabolism of raloxifene, quercetin, salbutamol, troglitazone using different in vitro systems. fraction metabolized by conjugation was estimated liver intestine, the importance multiple metabolic pathways on accuracy clearance prediction assessed. In intrinsic sulfation (CL<sub>int, SULT</sub>) determined human cytosol compared with microsomal glucuronidation UGT</sub>) CYP</sub>) expressed...
Interindividual variability in activity of uptake transporters is evident vivo, yet limited data exist vitro, confounding vitro-in vivo extrapolation. The kinetics seven organic anion-transporting polypeptide substrates was investigated over a concentration range plated cryopreserved human hepatocytes. Active clearance (CL<sub>active, u</sub>), bidirectional passive diffusion (<i>P</i><sub>diff</sub>), intracellular binding, and metabolism were estimated for bosentan, pitavastatin,...
Previous studies have shown the importance of addition albumin for characterization hepatic glucuronidation in vitro; however, no reports exist on effects renal or intestinal microsomal assays. This study characterized clearance (CL<sub>int, UGT</sub>) human kidney, liver, and microsomes presence absence bovine serum (BSA) seven drugs with differential UDP-glucuronosyltransferase (UGT) 1A9 UGT2B7 specificity, namely, diclofenac, ezetimibe, gemfibrozil, mycophenolic acid, naloxone, propofol,...
This white paper examines recent progress, applications, and challenges in predicting unbound total tissue intra/subcellular drug concentrations using vitro preclinical models, imaging techniques, physiologically based pharmacokinetic (PBPK) modeling. Published examples, regulatory submissions, case studies illustrate the application of different types data development to support modeling decision making for compounds with transporter-mediated disposition, likely disconnects between systemic...
Microphysiological systems (MPS) are complex and more physiologically realistic cellular in vitro tools that aim to provide relevant human data for quantitative prediction of clinical pharmacokinetics while also reducing the need animal testing.
Accounting for variability in plasma protein binding of drugs is an essential input to physiologically-based pharmacokinetic (PBPK) models special populations. Prediction fraction unbound (fu) such populations typically considers changes concentration while assuming that the affinity remains unchanged. A good correlation between predicted vs observed fu data reported various a given population often used as justification predictive methods. However, none these analyses evaluated prediction...