Background: AMG 517 or 1-aminobenzotriazole were quantified by LC-MS/MS from low blood/plasma volumes for rat pharmacokinetic (PK) characterization in order to qualify manual/automated dried blood spot (DBS) sampling and plasma separation capillary sampling. In addition, mouse serial automated blood sampling was compared with standard composite sampling.
Materials & Methods: AMG 517 or 1-aminobenzotriazole was administered to rats or mice and multiple microsampling techniques were used to obtain blood or plasma.
Results: PK parameters derived from DBS and whole blood-obtained drug concentrations were within 7% for manual DBS and 20% for automated DBS. Plasma PK parameters derived from capillary or standard plasma-obtained drug concentrations differed by 6%. Plasma PK parameters obtained from serial automated blood sampling or manual composite sampling were within 20%.
Conclusion: Collectively, these results suggest that the microsampling applications that were investigated are attractive approaches for quantifying drug candidates in low matrix volumes that can be successfully employed within discovery-stage rodent PK studies.
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http://dx.doi.org/10.4155/bio.14.184 | DOI Listing |
Drug Metab Dispos
June 2024
Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California (M.W., U.P.D.); Pharmacokinetics and Drug Metabolism, Syngene Amgen Research & Development Center, Bangalore, India (S.K., A.S., S.R.); and Amgen Research (K.R., T.O.) and Pharmacokinetics and Drug Metabolism (J.W.), Amgen Inc., Thousand Oaks, California
Free (unbound) drug concentration at the site of action is the key determinant of biologic activity since only unbound drugs can exert pharmacological and toxicological effects. Unbound drug concentration in tumors for solid cancers is needed to understand/explain/predict pharmacokinetics, pharmacodynamics, and efficacy relations. Fraction unbound ( ) in tumors is usually determined across several xenografted tumors derived from various cell lines in the drug discovery stage, which is time consuming and a resource burden.
View Article and Find Full Text PDFDrug Metab Dispos
October 2024
Bioimaging (F.X., T.G., M.R.G.), Nonclinical Safety (M.A.R.), and Immunology Research (A.I.W.), GlaxoSmithKline, Collegeville, Pennsylvania.
A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion.
View Article and Find Full Text PDFAAPS J
September 2023
Drug Metabolism & Pharmacokinetics Research Laboratories, Preclinical & Translational Sciences, Research, Takeda Pharmaceutical Company Limited, Shonan Health Innovation Park, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
Machine learning (ML) approaches have been applied to predicting drug pharmacokinetic properties. Previously, we predicted rat unbound brain-to-plasma ratio (Kpuu,brain) by ML models. In this study, we aimed to predict human Kpuu,brain through animal ML models.
View Article and Find Full Text PDFInt J Mol Sci
August 2023
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, Campus E8 1, 66123 Saarbrücken, Germany.
causes a wide range of infections, and it is one of the leading pathogens responsible for deaths associated with antimicrobial resistance, the rapid spread of which among urges the discovery of new antibiotics. The evaluation of in vivo efficacy of novel drug candidates is usually performed using animal models. Recently, zebrafish () embryos have become increasingly attractive in early drug discovery.
View Article and Find Full Text PDFFront Endocrinol (Lausanne)
November 2022
Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Objective: This study aimed to explore the associations of genetic variants in the semaphorin 3A (SEMA3A) signaling pathway genes, including , , , and with osteoporosis (OP) risk and bone mineral density (BMD) in a Chinese Han older adult population.
Study Design And Method: A two-stage design was adopted. Total of 47.
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