Fraction Unbound for Liver Microsome and Hepatocyte Incubations for All Major Species Can Be Approximated Using a Single-Species Surrogate
| العنوان: | Fraction Unbound for Liver Microsome and Hepatocyte Incubations for All Major Species Can Be Approximated Using a Single-Species Surrogate |
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| المؤلفون: | John T Barr, Upendra P. Dahal, Julie M. Lade, Thuy B. Tran |
| المصدر: | Drug Metabolism and Disposition. 47:419-423 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, Metabolic Clearance Rate, Pharmaceutical Science, Fraction (chemistry), 030226 pharmacology & pharmacy, Rats, Sprague-Dawley, Mice, 03 medical and health sciences, Dogs, 0302 clinical medicine, Species Specificity, Single species, In vivo, Drug Discovery, medicine, Animals, Humans, Pharmacology, biology, Chemistry, Haplorhini, biology.organism_classification, Small molecule, In vitro, Rats, medicine.anatomical_structure, Biochemistry, 030220 oncology & carcinogenesis, Hepatocyte, Hepatocytes, Microsomes, Liver, Microsome, Female |
| الوصف: | It is well recognized that nonspecific binding of a drug within an in vitro assay (fu) can have a large impact on in vitro to in vivo correlations of intrinsic clearance. Typically, this value is determined experimentally across multiple species in the drug-discovery stage. Herein we examine the feasibility of using a single species (rat) as a surrogate for other species using a panel of small molecules representing highly diverse structures and physiochemical classes. The study demonstrated that 86% and 92% of the tested compounds measured in the mouse, dog, monkey, and human were within 2-fold of rat values for fu in microsomes and hepatocytes, respectively. One compound, amiodarone, exhibited unique species-dependent binding where the fu was approximately 10-fold higher in human microsomes and 20-fold higher in human hepatocytes compared with the average of the other species tested. Overall, these data indicate that using a single species (rat) fu as a surrogate for other major species, including humans, is a means to increase the throughput of measuring nonspecific binding in vitro. |
| تدمد: | 1521-009X 0090-9556 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ee94fdb03246d7c18521dc9a64276c4c https://doi.org/10.1124/dmd.118.085936 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ee94fdb03246d7c18521dc9a64276c4c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1521009X 00909556 |
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