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Rapid Bioavailability and Disposition protocol: A novel higher throughput approach to assess pharmacokinetics and steady-state brain distribution with reduced animal usage by Fu, Tingting; Gao, Ruina; Scott-Stevens, Paul; Chen, Yan; Zhang, Chalmers; Wang, Jianfei; Summerfield, Scott; Liu, Houfu; Sahi, Jasminder is a Pharmacology, Toxicology and Pharmaceutics article available to read on EtoBox.
What is Rapid Bioavailability and Disposition protocol: A novel higher throughput approach to assess pharmacokinetics and steady-state brain distribution with reduced animal usage about?
Besides routine pharmacokinetic (PK) parameters, unbound brain-to-blood concentration ratio (K) is an index particularly crucial in drug discovery for central nervous system (CNS) indications. Despite advantages of K from steady state after constant intravenous (i.v.) infusion compared with one- or multiple time points after transient dosing, it is seldom obtained for compound optimization in early phase of CNS drug discovery due to requirement of prerequisite PK data to inform the study design. Here, we designed a novel rat in vivo PK protocol, dubbed as Rapid Bioavailability and Disposition (RBD), which combined oral (p.o.) dosing and i.v. infusion to obtain steady-state brain penetration, along with blood clearance, oral exposure and oral bioavailability for each discovery compound, within a 24 hour in-life experiment and only a few (e.g., 3) animals. Protocol validity was verified through simulations with a range of PK parameters in compartmental models as well as data comparison for nine compounds with distinct PK profiles. PK parameters (K, CL and oral AUC) measured from the RBD protocol for all compounds, were within two-fold and/or statistically similar to those derived fro
Who reads Rapid Bioavailability and Disposition protocol: A novel higher throughput approach to assess pharmacokinetics and steady-state brain distribution with reduced animal usage?
It is typically read by researchers, students, and practitioners in Pharmacology, Toxicology and Pharmaceutics.
- Author
- Fu, Tingting; Gao, Ruina; Scott-Stevens, Paul; Chen, Yan; Zhang, Chalmers; Wang, Jianfei; Summerfield, Scott; Liu, Houfu; Sahi, Jasminder
- Publisher
- Elsevier Science; Elsevier ; Elsevier BV (ISSN 0928-0987)
- Published
- 2018
- Language
- EN
- Field
- Pharmacology, Toxicology and Pharmaceutics (Life Sciences)