A5102785126- Pharmacogenetics and Drug Metabolism
- Metabolomics and Mass Spectrometry Studies
- Drug Transport and Resistance Mechanisms
- Analytical Chemistry and Chromatography
- DNA and Nucleic Acid Chemistry
- Metabolism and Genetic Disorders
- Drug-Induced Hepatotoxicity and Protection
- Microbial Natural Products and Biosynthesis
- Mass Spectrometry Techniques and Applications
- Advanced biosensing and bioanalysis techniques
- Synthetic Organic Chemistry Methods
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Marine Sponges and Natural Products
- Biochemical and Molecular Research
- RNA Interference and Gene Delivery
- Signaling Pathways in Disease
- Peptidase Inhibition and Analysis
- Protease and Inhibitor Mechanisms
- Chemical Reaction Mechanisms
- Synthesis and Catalytic Reactions
- Biosimilars and Bioanalytical Methods
- Spectroscopy Techniques in Biomedical and Chemical Research
- Melanoma and MAPK Pathways
- Pharmacological Effects and Assays
Roche (Switzerland)
2015-2024
Roche Pharma AG (Germany)
2019
Pfizer (United States)
2018
Bristol-Myers Squibb (Germany)
2018
Novartis (Switzerland)
2018
Chugai Pharma (United States)
2018
Roche (United States)
2018
Boehringer Ingelheim (Switzerland)
2018
Boehringer Ingelheim (Germany)
2011-2015
Boehringer Ingelheim (United States)
2015
Small wonder: Atrop-abyssomicin C is a small, yet complex spirotetronate (see scheme) that active against Gram-positive bacteria, such as MRSA. Feeding studies and genetic manipulation of its producer, Verrucosispora maris AB-18-032, for the first time give insight into biosynthesis demonstrate how closely related members this important class molecules are.
Antisense oligonucleotides linked by phosphorothioates are an important class of therapeutics under investigation in various pharmaceutical companies. may be coupled to high-affinity ligands (triantennary N-acetyl galactosamine = GalNAc) for hepatocyte-specific asialoglycoprotein receptors (ASGPR) enhance uptake hepatocytes and increase potency. Since disposition biotransformation GalNAc-conjugated is different from unconjugated oligonucleotides, appropriate analytical methods required...
Subtle restraint: Abyssomicin C and atrop-abyssomicin are polyketide-type antibiotics produced by the marine actinomycete of genus Verrucosispora. Investigations functional pathway show that a subunit 4-amino-4-deoxychorismate synthase from Bacillus subtilis is irreversibly inhibited through covalent binding to side chain Cys 263, undergoing rearrangement structure abyssomicin D type (see scheme).
For therapeutic proteins, the currently established standard development path generally does not foresee biotransformation studies by default because it is well known that clearance of proteins proceeds via degradation to small peptides and individual amino acids. In contrast molecules, there no general need identify enzymes involved in this information relevant for drug-drug interaction assessment understanding a protein. Nevertheless, are good reasons embark on studies, especially complex...
This article describes the combination of whole-body autoradiography with liquid extraction surface analysis (LESA) and mass spectrometry (MS) to study distribution tachykinin neurokinin-1 antagonist figopitant its metabolites in tissue sections rats after intravenous administration 5.0 mg/kg figopitant. An overview results is presented together identification semiquantification parent drug based on LESA-MS. The quality accuracy data generated by LESA-MS were assessed comparison classic...
Idiosyncratic drug toxicity is a major challenge for the pharmaceutical industry since complex and multifactorial steps are involved, dose-dependency unclear, its occurrence not reliably predictable. Whereas exact mechanisms leading to idiosyncratic remain elusive in many cases, there often hints at involvement of reactive metabolites, such as acyl glucuronides formed by conjugation carboxylic acids with glucuronic acid. Because patient-related susceptibilities sufficiently understood, best...
The in vivo biotransformation of a novel fusion protein tetranectin/apolipoprotein A1 (TN-ApoA1) was investigated by ligand-binding mass spectrometry (LB-MS) support enzyme-linked immunosorbent assays (ELISA). main focus on catabolites formed proteolysis the rabbit following intravenous administration lipidated TN-ApoA1. drug and its were isolated from plasma immunocapture with monoclonal antibody (mAb) binding to region captured released streptavidin-coated magnetic beads, separated...
There is an increasing demand for quantitative data on metabolite exposure triggered by regulatory guidances. This contribution describes the accuracy of nanoelectrospray ionization mass spectrometry response drug compounds and their metabolites from biological matrices compared with radiometric quantification. a comprehensive investigation set real-life pharmaceutical in relevant such as urine, bile, feces plasma. The suggest that can be used semi-quantitation absence reference standards....
1. The emerging technique of employing intravenous microdose administration an isotope tracer concomitantly with [14C]-labeled oral dose was used to characterize the disposition and absolute bioavailability a novel metabotropic glutamate 5 (mGlu5) receptor antagonist under clinical development for major depressive disorder (MDD). 2. Six healthy volunteers received single 1 mg [12C/14C]-basimglurant (2.22 MBq) concomitant i.v. 100 μg [13C6]-basimglurant. Concentrations [12C]-basimglurant...
Chorismate is an important and central metabolite branching off to the biosyntheses of aromatic amino acids p-aminobenzoic acid (pABA), a component vitamin folic acid. Here we report on novel variation unified catalytic mechanism in Bacillus subtilis pABA biosynthesis that includes formation new intermediate, 2-amino-2-deoxyisochorismate (ADIC), thus significantly differing from Escherichia coli. In B. subtilis, chorismate converted ADIC, which catalyzed by aminodeoxychorismate synthase...
A number of drugs can cause precipitates within renal tubules leading to crystal nephropathy. Crystal nephropathy is usually an exposure-related finding and not uncommon in preclinical studies, where high doses are tested. An understanding the nature important for human risk assessment further development. Our aim was investigate ability various imaging techniques detect presence or metabolites crystals. We applied matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron...
Antisense oligonucleotides (ASOs) are chemically modified nucleic acids with therapeutic potential, some of which have been approved for marketing. We performed a study in rats to investigate mechanisms toxicity after administration 3 tool locked acid (LNA)-containing ASOs differing established safety profiles. Four male per group were dosed once, 3, or 6 times subcutaneously, 7 days between dosing, and sacrificed the last dose. These either unconjugated (naked) conjugated...
Subtile Hemmung: Abyssomicin C und atrop-Abyssomicin sind Antibiotika vom Polyketid-Typ, die beide von marinen Actinomyceten der Gattung Verrucosispora produziert werden. Studien zum Wirkmechanismus belegen, dass eine Untereinheit 4-Amino-4-desoxychorismat-Synthase aus Bacillus subtilis durch kovalente Bindung an Seitenkette Cys 263 irreversibel inhibiert wird, wobei Umlagerung zu einer Struktur ähnlich D stattfindet (siehe Schema).
While there are dedicated guidelines for industry regarding the assessment of genotoxic potential new pharmaceuticals and impurities, general safety major drug metabolites, only limited guidance exists on minor metabolites. In this Perspective, we discuss challenges associated with assessing human metabolites share five case studies within context an "aware–avoid–assess" paradigm. A special focus is a class potentially carcinogens, aromatic amines (arylamines anilines). This compound...
The metabolism, pharmacokinetics, excretion and distribution of a sodium-glucose co-transporter (SGLT 2) inhibitor, empagliflozin, were studied in mice, rats beagle dogs following single oral or intravenous administration [ 14 C]-empagliflozin.Empagliflozin was well absorbed all species after administration.The clearance empagliflozin low dog moderate mice rats.Volume half-life generally species.Oral bioavailability (31%) high (90-97%) (89%).The pharmacokinetics C]-empagliflozin-related...
1. In recent years, the minipig is increasingly used as a test species in non-clinical assessment of drug candidates. While there good scientific evidence available concerning cytochrome P450-mediated metabolism minipig, knowledge other metabolic pathways more limited. 2. The aim this study was to provide an understanding when, why, and how differs from commonly studies. In-house cross-species metabolite profile comparisons hepatocytes microsomes 38 Roche development compounds were...
Abstract As more and protein biotherapeutics enter the drug discovery pipelines, there is an increasing interest in tools for mechanistic metabolism investigations of biologics order to identify prioritize most promising candidates. Understanding or even predicting vivo clearance support translational pharmacokinetic modeling activities essential, however a lack effective validated vitro cellular tools. Although different mechanisms have be adressed context disposition, scope not comparable...
Abstract Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with V600 mutation–positive unresectable or metastatic melanoma and Erdheim‐Chester disease. This phase 1, open‐label, single‐arm study was designed to estimate absolute bioavailability oral vemurafenib at steady state characterize pharmacokinetics single intravenous microdose 14 C‐labeled in malignancies. Patients received 960 mg twice daily on days 1 through 28, infusion solution (3 mL, corresponding...