Muscle to Brain Partitioning as Measure of Transporter-Mediated Efflux at the Rat Blood–Brain Barrier and Its Implementation into Compound Optimization in Drug Discovery
| Autor: | Achim Sauer, Hermann Rapp, Anneke Himstedt, Klaus Klinder, Yunhai Cui, Ralf Lotz |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
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Pharmaceutical Science lcsh:RS1-441 Pharmacology Blood–brain barrier blood–brain barrier 030226 pharmacology & pharmacy Article drug discovery lcsh:Pharmacy and materia medica 03 medical and health sciences 0302 clinical medicine in vitro–in vivo correlation In vivo medicine CNS drug biology Chemistry Drug discovery Kp uu brain screening bcrp efflux kp uu brain drug partitioning cns drug screening drug discovery in vitro–in vivo correlation In vitro toxicology Skeletal muscle Transporter p-gp drug partitioning efflux medicine.anatomical_structure biology.protein BCRP Efflux 030217 neurology & neurosurgery |
| Zdroj: | Pharmaceutics, Vol 11, Iss 11, p 595 (2019) Pharmaceutics Volume 11 Issue 11 |
| ISSN: | 1999-4923 |
| Popis: | Movement of xenobiotic substances across the blood&ndash brain barrier (BBB) is tightly regulated by various transporter proteins, especially the efflux transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). Avoiding drug efflux at the BBB is a unique challenge for the development of new central nervous system (CNS) drugs. Drug efflux at the BBB is described by the partition coefficient of unbound drug between brain and plasma (Kp,uu,brain) which is typically obtained from in vivo and often additionally in vitro measurements. Here, we describe a new method for the rapid estimation of the in vivo drug efflux at the BBB of rats: the measurement of the partition coefficient of a drug between brain and skeletal muscle (Kp,brain/muscle). Assuming a closely similar distribution of drugs into the brain and muscle and that the efflux transporters are only expressed in the brain, Kp,brain/muscle, similar to Kp,uu,brain, reflects the efflux at the BBB. The new method requires a single in vivo experiment. For 64 compounds from different research programs, we show the comparability to other approaches used to obtain Kp,uu,brain. P-gp- and BCRP-overexpressing cell systems are valuable in vitro tools for prescreening. Drug efflux at the BBB can be most accurately predicted based on a simple algorithm incorporating data from both in vitro assays. In conclusion, the combined use of our new in vivo method and the in vitro tools allows an efficient screening method in drug discovery with respect to efflux at the BBB. |
| Databáze: | OpenAIRE |
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