Drug transporters which are found in various tissues can have a significant effect on the ADMET and pharmacokinetics (PK) properties of new drugs. For example, for CNS targeted therapeutics, distribution into the brain can be greatly limited by efflux transport at the blood-brain barrier. For other drugs, oral bioavailability can be affected by limited intestinal absorption or pronounced biliary elimination. While cell-based systems can provide mechanistic insights useful for screening studies, whole animal studies provide the most translational results. Until now, in vivo studies were limited to using chemical inhibitors in wild type animals. Unfortunately, these chemical inhibitors often interact with multiple transporters, confounding data interpretation and resulting in assay systems that are less than definitive. Single transporter knockout rats serve as more specific, definitive tools for predictive ADMET studies.
Working with our partner, InterVivo Solutions, we've harnessed our unique SAGE® transporter knockout rat models to provide a complete assessment of transporter activity resulting in more translational and clear data interpretation.
Figure 1. Influence of P-gp on quinidine CSF concentration. Mean + S.D. (n=5) unbound plasma and CSF concentrations of quinidine in wild type (WT) and Mdr1a knockout (KO) rats over time following i.v. administration of a loading dose (6 mg/kg) and constant rate infusion (27.9 µg/min/kg) of quinidine.