Predictive in vivo studies utilizing our suite of transporter knockout rats

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 in vitro or cell-based systems can provide mechanistic insights useful for screening type 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 transporter knockout rat models to provide a complete assessment of transporter activity resulting in more translational and clear data interpretation.

Simply send us your compound and we'll assay the effect of P-gp, Bcrp, or Mrp2 on the PK properties of your compound.

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We'll provide:

  • n = 4 transporter knockout rats from one of our lines (P-gp, Bcrp, or Mrp)and n = 4 wild-type controls
  • Dosing via IV, IP, PO, or SC routes (other routes available)
  • IV dosing via jugular or femoral vein catheter
  • Sampling of blood/plasma via carotid or femoral artery catheter
  • Discrete serial CSF sampling via cisterna magna catheter together with blood/plasma sampling in the same animals
  • Dosing and sampling of 8 standard time points up to 24 hours post-dose

Also included is our Bioanalysis and Expert PK Analysis:

  • LC-MS/MS method development and qualification for the test article
  • Processing and analysis of plasma/CSF samples
  • Pharmacokinetics analysis and reporting

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ADME efflux
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.