A5013278963- Drug Transport and Resistance Mechanisms
- Pharmacogenetics and Drug Metabolism
- Receptor Mechanisms and Signaling
- Computational Drug Discovery Methods
- Pharmacological Effects and Toxicity Studies
- Statistical Methods in Clinical Trials
- Nitric Oxide and Endothelin Effects
- Neuropeptides and Animal Physiology
- Analytical Chemistry and Chromatography
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Regulation of Appetite and Obesity
- Parathyroid Disorders and Treatments
- Diabetes Treatment and Management
- Pharmacological Effects and Assays
- Drug-Induced Hepatotoxicity and Protection
- Eicosanoids and Hypertension Pharmacology
- Metabolism, Diabetes, and Cancer
- Neurotransmitter Receptor Influence on Behavior
- Epilepsy research and treatment
- Liver Disease Diagnosis and Treatment
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Pancreatic function and diabetes
- Innovative Microfluidic and Catalytic Techniques Innovation
- Adipose Tissue and Metabolism
Pfizer (United States)
2016-2025
University of Michigan
2015
Renewable Energy Systems (United States)
2015
University of California, San Francisco
2015
World Wide Web Consortium
2014
Foton Motors (China)
2012
University at Buffalo, State University of New York
1996-2000
Kobe Pharmaceutical University
2000
Abstract Relative plasma, brain and cerebrospinal fluid (CSF) exposures unbound fractions in plasma were examined for 18 proprietary compounds rats. The relationship between vivo brain‐to‐plasma ratio vitro plasma‐to‐brain fraction (fu) was examined. In addition, fu their to CSF‐to‐plasma CSF‐to‐brain ratios, respectively. Findings delineated based on the presence or absence of active efflux. Finally, same comparisons FVB vs. MDR 1a/1b knockout mice a selected P‐glycoprotein (Pgp) substrate....
Quantitative prediction of human pharmacokinetics is critical in assessing the viability drug candidates and determining first‐in‐human dosing. Numerous methodologies, incorporating both vitro preclinical vivo data, have been developed recent years, each with advantages disadvantages. However, lack a comprehensive data set, clinical, has limited efforts to evaluate optimal strategy (or strategies) that results quantitative predictions pharmacokinetics. To address this issue, authors...
Volume of distribution is one the most important pharmacokinetic properties a drug candidate. It major determinant half-life and dosing frequency drug. For similar log P, basic molecule will tend to exhibit higher volume than neutral molecule. Acids often low volumes distribution. Although design strategy against can be advantageous in achieving desirable regimen, it must well-directed order avoid detrimental effects other properties. Strategies increase include adding lipophilicity...
More than 15 years have passed since the first description of unbound brain-to-plasma partition coefficient (Kp,uu,brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support notion that (free) concentration a drug at site action, such as brain, is driving force for pharmacological responses. Towards this end, Kp,uu,brain key parameter obtain brain...
The P-glycoprotein (P-gp)-deficient mouse model is used to assess the influence of P-gp-mediated efflux on central nervous system (CNS) distribution drugs. steady-state unbound plasma/unbound brain concentration ratio ([plasma],<sub>u</sub>/[brain],<sub>u</sub>) an alternative method for assessing CNS drugs independent mechanism(s) involved. objective this study was compare degree distributional impairment determined from in vivo P-gp with that [plasma],<sub>u</sub>/[brain],<sub>u</sub>...
Unbound fractions in mouse brain and plasma were determined for 31 structurally diverse central nervous system (CNS) drugs two active metabolites. Three comparisons made between vitro binding vivo exposure data, namely: 1) brain-to-plasma versus unbound plasma-to-unbound fraction ratio (fu<sub>plasma</sub>/fu<sub>brain</sub>), 2) cerebrospinal fluid-to-brain (fu<sub>brain</sub>), 3) fluid-to-plasma (fu<sub>plasma</sub>). data within 3-fold of ratios the majority examined (i.e., 22 33),...
Although approaches to the prediction of drug-drug interactions (DDIs) arising via time-dependent inactivation have recently been developed, such do not account for simple competitive inhibition or induction. Accordingly, these provide accurate predictions DDIs from (e.g., ketoconazole) induction cytochromes P450 phenytoin). In addition, methods that focus upon a single interaction mechanism are likely yield misleading in face mixed mechanisms ritonavir). As such, we developed more...
Drug half-life has important implications for dosing regimen and peak-to-trough ratio at the steady state. A of 12-48 h is generally ideal once daily oral drugs. If too short, it may require more frequent in order to maintain desired exposures avoid unnecessarily high peak concentrations. This pose challenges achieving optimal efficacy, safety, patient compliance. long, time over which accumulation subsequent elimination occur be prolonged. problems with managing adverse effects design...
Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, human dose predictions related 4. This compound demonstrated robust urinary excretion in rats an excellent safety profile. It is currently phase clinical trials being evaluated for treatment type diabetes.
Cytochrome P4503A4 (CYP3A4) is the principal drug-metabolizing enzyme in human liver. Drug-drug interactions (DDIs) caused by induction of CYP3A4 can result decreased exposure to coadministered drugs, with potential loss efficacy. Immortalized hepatocytes (Fa2N-4 cells) have been proposed as a tool identify inducers. The purpose current studies was characterize effect known inducers on Fa2N-4 cells, and determine whether these vitro data could reliably project magnitude DDIs induction....
Small vessel vasculitis is a life-threatening condition and patients typically present with renal pulmonary injury. Disease pathogenesis associated neutrophil accumulation, activation, oxidative damage, the latter being driven in large part by myeloperoxidase (MPO), which generates hypochlorous acid among other oxidants. MPO has been vasculitis, disseminated vascular inflammation involving microvasculature often resulting critical consequences. contributes to injury 1) catabolizing nitric...
The efficacious dose of a drug is perhaps the most holistic metric reflecting its therapeutic potential. Dose predicted at many stages in discovery and development. Prior to 1990s, prediction was limited "working" reasonable regimen an animal model. Through early 2000s, predictions were generated candidate nomination then refined during clinical Currently, can be made enable design. this stage identify critical properties for viable provide clinically relevant context lead optimization. In...
Because of the importance intracellular unbound drug concentrations in prediction vivo that are determinants efficacy and toxicity, a number assays have been developed to assess vitro drugs. Here we present rapid method determine cultured cells, apply along with mechanistic model predict metformin subcellular compartments stably transfected human embryonic kidney 293 (HEK293) cells. Intracellular space (ICS) was calculated by subtracting [<sup>3</sup>H]-inulin distribution volume...
Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests causal role for MPO in various autoimmune and inflammatory disorders including vasculitis cardiovascular Parkinson's diseases, implying inhibitors may represent therapeutic treatment option. Herein, we present design, synthesis, preclinical evaluation N1-substituted-6-arylthiouracils as potent selective MPO. Inhibition proceeded time-dependent manner by covalent,...
Estimation of unbound fraction substrate in microsomal incubation media is important accurately predicting hepatic intrinsic clearance and drug-drug interactions. In this study, the 1223 drug-like molecules human liver has been determined using equilibrium dialysis. These compounds, which include 27 marketed drug molecules, cover a much broader range physiochemical properties such as hydrophobicity, molecular weight, ionization state, degree binding than those examined previous work....
The mineralocorticoid receptor (MR) antagonists PF 03882845 and eplerenone were evaluated for renal protection against aldosterone mediated disease in uninephrectomized Sprague Dawley (SD) rats maintained on a high salt diet receiving by osmotic mini pump 27 days. Serum K+ the urinary albumin to creatinine ratio (UACR) assessed following 14 days of treatment. Aldosterone induced fibrosis as evidenced increases UACR, collagen IV staining kidney cortex, expression pro fibrotic genes relative...
Understanding the quantitative implications of P-glycoprotein and breast cancer resistance protein efflux is a key hurdle in design effective, centrally acting or restricted therapeutics. Previously, comprehensive physiologically based pharmacokinetic model was developed to describe vivo unbound brain-to-plasma concentration ratio as function activity measured vitro. In present work, predictive utility this framework examined through application vitro data generated on 133 unique compounds...
A previously developed physiologically based pharmacokinetic model for hepatic transporter substrates was extended to an organic anion transporting polypeptide substrate, telmisartan. Predictions used in vitro data from sandwich culture human hepatocyte and liver microsome assays. We have a novel method calibrate partition coefficients (<i>Kp</i>s) between nonliver tissues plasma on the basis of published positron emission tomography (PET) decrease uncertainty tissue distribution introduced...
Additional Supporting Information may be found in the online version of this article. Supplementary Table 1. Summary victim DDIs with rifampicin as inhibitor – OATP1B1/1B3. 2. cyclosporine OATP1B1/1B3, P-gp and BCRP. 3. probenecid OAT1/3. 4. cimetidine OCT2/MATEs. Please note: The publisher is not responsible for content or functionality any supporting information supplied by authors. Any queries (other than missing content) should directed to corresponding author