ADME and Predictive Toxicology Workshop

Transporter knock-out animal models offer an in vivo tool to study the functional consequences on pharmacokinetics of potential drug efflux. With the recent advent of genetically P-gp (MDR1) or BCRP (ABCG2) deficient rat models, species comparison may also be performed towards commonly used mice knock-out models. The currents sets of experiments investigated the P-gp mediated efflux at the blood-brain barrier (BBB) for a set of known substrates applying brain and plasma drug exposure measurements in genetically modified Mdr1a knock-out rats and mice. Comparisons were also made towards chemically induced P-gp inhibition by administration of the P-gp inhibitor zosuquidar. P-gp substrates displayed significantly higher brain-to-plasma distribution in both P-gp knock-out rats and mice compared to their wild-type counterparts and substantial quantitative species overlap in P-gp functionality was observed among all tested compounds. In vivo studies with BCRP knock-out mice showed a modest difference in brain-to-plasma distribution between BCRP knock-out and wild-types for the tested substrates. Systemically, in plasma, significant difference was observed on oral bioavailability between BCRP knock-out and wild-type mice for some substrates whereas others did not exhibit any differences in the plasma concentration-time course between genotypes. These findings were mirrored in experiments performed in BCRP knock-out and wild-type rats. P-gp and BCRP knock-out rodent models were shown to be applicable for functional quantitative assessments of ADME properties in vivo related to these transporters.

Workshop Tutor Christoffer Bundgaard Principal Scientist, H. Lundbeck A/S