Fraction Unbound for Liver Microsome and Hepatocyte Incubations for All Major Species Can Be Approximated Using a Single-Species Surrogate
Autor: | John T Barr, Upendra P. Dahal, Julie M. Lade, Thuy B. Tran |
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Rok vydání: | 2019 |
Předmět: |
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 |
Zdroj: | Drug Metabolism and Disposition. 47:419-423 |
ISSN: | 1521-009X 0090-9556 |
Popis: | 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. |
Databáze: | OpenAIRE |
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