Key determinants of the circulatory exposure of organic anions: differences in hepatic uptake between multidrug resistance-associated protein 2 (Mrp2)-deficient rats and wild-type rats.

1. Raloxifene-6-glucuronide (R6G) is a substrate of rat multidrug resistance-associated protein 2 (Mrp2), a transporter responsible for biliary excretion of organic anions. 2. Pharmacokinetic modeling of R6G in Eisai hyperbilirubinemic rats (EHBRs), hereditary Mrp2-deficient rats, and wild-type Sprague-Dawley rats (SDRs) indicated that reduction in not only biliary excretion but also hepatic uptake of R6G influenced low clearance in EHBRs. 3. An integration plot study demonstrated that the hepatic uptake of R6G was 66% lower in EHBRs than that in SDRs. A reduction was observed for the other Mrp2 substrate Valsartan (95% lower) but not for estradiol-17ß-glucuronide (E217ßG). This variation may be associated with the difference in substrate specificity of transporters and/or inhibition of hepatic uptake of organic anions by endogenous substances such as bilirubin glucuronides. 4. In conclusion, incidental alteration of the hepatic uptake of organic anions should be considered as an explanation of their enhanced systemic exposure in EHBRs.

Advancing novel therapies for neurodegeneration through an innovative model for industry-academia collaborations: A decade of the Eisai-UCL experience.

External innovation initiatives in the pharmaceutical industry have become an integral part of research and development. Collaborations have been built to enhance innovation, mitigate risk, and share cost, especially for neurodegenerative diseases, a therapeutic area that has suffered from high attrition rates. This article outlines the Eisai-University College London (UCL) Drug Discovery and Development Collaboration as a case study of how to implement a productive industry-academic partnership. In the first 10 years, seven projects have been established and the first project, a novel anti-tau antibody for Alzheimer's disease, has entered clinical trials, providing early validation of this collaboration model.