A5070904782- Pharmacogenetics and Drug Metabolism
- Analytical Chemistry and Chromatography
- Metabolomics and Mass Spectrometry Studies
- Mass Spectrometry Techniques and Applications
- Drug Transport and Resistance Mechanisms
- Adenosine and Purinergic Signaling
- Pharmacological Effects and Toxicity Studies
- Renal Transplantation Outcomes and Treatments
- Drug-Induced Hepatotoxicity and Protection
- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- 3D Printing in Biomedical Research
- Receptor Mechanisms and Signaling
- Estrogen and related hormone effects
- Cancer therapeutics and mechanisms
- Chemical Reactions and Isotopes
- Liver physiology and pathology
- Microfluidic and Capillary Electrophoresis Applications
- Renal Diseases and Glomerulopathies
- Cancer-related Molecular Pathways
- Sulfur Compounds in Biology
- Conducting polymers and applications
- Nerve injury and regeneration
- Pesticide Residue Analysis and Safety
- Graphene and Nanomaterials Applications
Janssen (United States)
2012-2025
Johnson & Johnson (United States)
2005-2021
Springhouse
2013-2019
Vertex Pharmaceuticals (United States)
2015
AstraZeneca (United States)
2015
Daiichi Sankyo (United States)
2015
Brown University
2014
University of Illinois Urbana-Champaign
2014
University of Illinois Chicago
2014
Princeton University
1995-2004
A rat, dog, and human Liver-Chip designed using microengineered Organs-on-Chips technology recapitulates species-specific drug toxicities.
Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) has been generally understood several years, significant advances have made only in past few years regarding how vitro time-dependent data used to understand and predict clinical DDI. In this article, a team...
Abstract Performance evaluation of accurate mass measurement by the LTQ/Orbitrap, at a resolving power 60 000 and in external calibration mode, indicated that Orbitrap is capable providing high accuracy <2 ppm for over 24 h post‐calibration. This, together with limited trade‐off between sensitivity plus wide dynamic range accuracy, suggested LTQ/Orbitrap an ideal analytical tool structural elucidation metabolites. The application to identification human liver microsomal metabolites...
TAK-875, a GPR40 agonist, was withdrawn from Phase III clinical trials due to drug-induced liver injury (DILI). Mechanistic studies were conducted identify potential DILI hazards (covalent binding burden (CVB), hepatic transporter inhibition, mitochondrial toxicity, and toxicity in rats) associated with TAK-875. Treatment of hepatocytes radiolabeled TAK-875 resulted CVB 2.0 mg/day, which is above the threshold 1 mg/day considered be risk for DILI. Covalent formation reactive acyl glucuronide...
Abstract Non‐covalent binding of antibiotics to their target ligands represents a form molecular recognition which is considerable contemporary interest in bioorganic and bioanalytical chemistry. The vancomycin antibiotics, including ristocetin, are family complex glycopeptides bind specifically the C ‐terminal sequence X‐D‐Ala‐D‐Ala, where × L ‐lysine, ‐diaminopimelic acid, ‐alanine or ‐homoserine. It shown that non‐covalent complexation ristocetin with peptide solution, key phenomenon...
A need still exists for a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method that can detect broad classes of glutathione (GSH) conjugates and provide characterization their structures. We now describe the development multiplexes high-resolution accurate analysis with isotope pattern triggered data-dependent product ion scans, simultaneous detection structural elucidation GSH within single using LTQ/Orbitrap. This was initially developed to generated from incubating 10 microM...
A strategy is proposed to profile compounds for mechanism-based inactivation of CYP3A4, CYP2C19, CYP2C9, CYP2D6, and CYP1A2 based on an apparent partition ratio screen. Potent positives from the screen are confirmed by time- concentration-dependent assays. Quasi-irreversible inhibitions then differentiated irreversible inactivations oxidation with potassium ferricyanide and/or dialysis. The three-step screening procedure has been validated acceptable accuracy precision detection confirmation...
Drug toxicity during the development of candidate pharmaceuticals is leading cause discontinuation in preclinical drug discovery and development. Traditionally, often determined by histological examination, clinical pathology, detection drugs and/or metabolites liquid chromatography–mass spectrometry (LC-MS). While these techniques individually provide information on pathological effects metabolites, they cannot specific molecular spatial without additional experiments. Matrix-assisted laser...
The bioavailability of an oral nonaqueous solution sirolimus was compared under fasting conditions and after a high‐fat meal in randomized, two‐way crossover pharmacokinetic study. Healthy volunteers were administered 15 mg single dose on two occasions, once while consumption breakfast. Whole blood concentrations assayed by using validated method with high‐performance liquid chromatography/tandem mass spectrometric detection. Sirolimus absorbed more slowly when than fasting, as shown...
The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for disease. Further revealed that it metabolized to reactive intermediates caused the genotoxicity Ames mouse lymphoma L51784 assays. identification metabolites enabled preparation two optimized compounds 13 14 were devoid metabolic liabilities associated with 1. Compounds are potent have...
Recent European Medicines Agency (final) and US Food Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug (DDI) potential if present at ≥ 25% of the parent area under time-concentration curve (AUC) (US Administration) or 10% total drug-related AUC (European Agency). To examine application these regulatory recommendations, a group scientists, representing 18 pharmaceutical companies Metabolism...
2-Amino-4-phenyl-8-pyrrolidin-1-ylmethyl-indeno[1,2-d]pyrimidin-5-one (1) is a novel and potent selective dual A2A/A1 adenosine receptor antagonist from the arylindenopyrimidine series that was determined to be genotoxic in both Ames Mouse Lymphoma L5178Y assays only following metabolic activation. Compound 1 identified as frame-shift mutagen Salmonella typhimurium tester strain TA1537 indicated by significant dose-dependent increase revertant colonies compared vehicle control. The...
A LC−LC/MS/MS method has been developed that significantly increases the throughput in metabolism screening of drug candidates during lead optimization discovery. This was accomplished by reduction sample preparation time through an on-line extraction a and its metabolites from microsomal proteins using turbulent flow chromatography. Following injection onto column at flow, are backwashed reverse-phase via switching resolved chromatographically laminar 2 mL/min. tandem turbulent-laminar...
Using Caco-2 cell monolayers expressing CYP3A4, we investigated the interplay between metabolism and transport on first-pass intestinal extraction of immunosuppressant sirolimus, a CYP3A4/P-glycoprotein (P-gp) substrate. Modified cells metabolized [(14)C]sirolimus to predicted amounts CYP3A4-mediated products based CYP3A4 content, which was approximately 20% that measured in human small mucosal homogenate. [(14)C]Sirolimus also degraded known ring-opened product, seco-rapamycin....
Frozen storage of minced Greenland halibut (Reinhardtius hippoglossoides) at -10°C resulted in a rapid loss salt solubility “my ofibrillar proteins” (approximately 50% 15 days) and gradual water “sarcoplasmic 40% 120 days). The inextractable protein from frozen mince (R) was completely soluble 4% sodium dodecylsulfate (SDS) when disulfide bond reducing agent such as mercaptoethanol (ME) present. Other reagents, including urea Triton X 100, were less effective solubilizing the after storage....
Eighteen adult subjects with mild to moderate hepatic impairment and 18 healthy control were given a single 15-mg dose of sirolimus by oral solution. Mean whole-blood weight-normalized oral-dose clearances (CL/F) significantly decreased (P = .02) in -31.8% -36.0%, respectively, compared controls. There no significant differences mean C(max) t(max) values among groups. The observed decreases CL/F may be relevant renal transplant patients impairment, based on the close similarity controls...
JNJ-10450232 (NTM-006), a novel non-opioid, non-nonsteroidal anti-inflammatory drug with structural similarities to acetaminophen, demonstrated anti-pyretic and/or analgesic activities in preclinical models and humans reduced potential cause hepatotoxicity species. Metabolism disposition of (NTM-006) following oral administration rats, dogs, monkeys are reported. Urinary excretion was the major route elimination based on recovery 88.6% (rats) 73.7% (dogs) dose. The compound extensively...
The pharmacokinetics and metabolic disposition of sirolimus (rapamycin, Rapamune), a macrocyclic immunosuppressive agent for the prevention allograft rejection in organ transplantation, were investigated 6 healthy male volunteers after single nominal 40-mg oral dose 14C-radiolabeled drug, with added aim assessing potential role metabolites clinical pharmacology parent drug. absorption drug derived materials was rapid (tmax 1.3 ± 0.5 hours, mean SD), elimination slow (t½ 60 10 SD) whole...