November 08, 2017
It is well established in CNS drug discovery and development that Multi Drug Resistance Protein 1 (MDR1, ABCB1, also known as P-glycoprotein or P-gp) and more recently the Breast Cancer Resistance Protein (BCRP, ABCG8) are important modulators of CNS drug exposure. This is because of their localisation to the apical membrane of the cells lining the blood-brain barrier (BBB), and their ability to limit cell penetration of their substrates, effectively excluding them from the brain, in this instance. The actions of these transporters can be very profound, rendering many potential CNS-target drugs useless in clinical use. It is commonplace in drug discovery and development to rely on in vitro measures of MDR1 and BCRP substrate activity to drive candidate selection strategies. Whilst it is reported that there is generally good agreement between the human-based in vitro tests and the preclinical animal models, this is by no means always the case, and there is always a degree of concern that useful clinical candidates may be rejected due to species differences in substrate activity. LLC-PK1 and MDCK(II) cells (porcine and canine kidney cell lines, respectively) transfected with one or other of the human transporters are most typically used to assess P-gp and BCRP interactions, in vitro. In vivo preclinical assessments of CNS penetration are typically executed in rat and/or genetically modified mouse models. Additionally, it is possible that endogenous expression of non-human transporter in the background cell lines may give rise to false positive outcomes.
Solvo has developed and characterised a set of in vitro tools to study human MDR1, human BCRP, rMdr1a, rBcrp, mMdr1a, and mBcrp in the same standard monolayer format, and using the same background cell line (LLC-PK1 for P-gp and MCDKII for BCRP).