title: Insights From an Integrated Physiologically Based Pharmacokinetic Model for Brain Penetration.
abstract: Central-nervous-system, physiologically based pharmacokinetic (PBPK) models predict exposure profiles in the brain, that is, the rate and extent of distribution. The current work develops one such model and presents improved methods for determining key input parameters. A simple linear regression statistical model estimates the passive permeability at the blood-brain barrier from brain uptake index data and descriptors, and a novel analysis extracts the relative active transport parameter from in vitro assays taking into consideration both paracellular transport and unstirred water layers. The integrated PBPK model captures the concentration profiles of both rate-restricted and effluxed compounds with high passive permeability. In many cases, compounds distribute rapidly into the brain and are, therefore, not rate limited. The PBPK model is then simplified to a straightforward equation to describe brain-to-plasma ratios at steady state. The equation can estimate brain penetration either from in vitro efflux data or from in vivo results from another species and, therefore, is a valuable tool in the discovery setting.
authors: Department of Pharmacokinetics, Dynamics, and Metabolism, Worldwide Research and Development, Pfizer, Inc., 610 Main Street, Cambridge, Massachusetts 02139. Electronic address: patrick.trapa@pfizer.com.
authors: Patrick E
authors: PE
authors: Trapa
authors: Department of Pharmacokinetics, Dynamics, and Metabolism, Worldwide Research and Development, Pfizer, Inc., 610 Main Street, Cambridge, Massachusetts 02139.
authors: Elena
authors: E
authors: Belova
authors: Department of Pharmacokinetics, Dynamics, and Metabolism, Worldwide Research and Development, Pfizer, Inc., 610 Main Street, Cambridge, Massachusetts 02139.
authors: Jenny L
authors: JL
authors: Liras
authors: Department of Pharmacokinetics, Dynamics, and Metabolism, Worldwide Research and Development, Pfizer, Inc., 610 Main Street, Cambridge, Massachusetts 02139.
authors: Dennis O
authors: DO
authors: Scott
authors: Department of Pharmacokinetics, Dynamics, and Metabolism, Worldwide Research and Development, Pfizer, Inc., 610 Main Street, Cambridge, Massachusetts 02139.
authors: Stefan J
authors: SJ
authors: Steyn
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D010599:Pharmacokinetics; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations
keywords: blood-brain barrier; distribution; efflux pumps; in vitro models; mathematical models; physiologically based pharmacokinetic models