Drug Transporter Studies

Predictive In Vivo Drug Transporter Studies with SAGE® ADMET Rat


As part of our commitment to offering predictive in vivo models, we have partnered with SAGE® Labs to offer advanced Efficacy and PK studies using their next-generation animal models, including the industry first and only knockout rat model.

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.

Current practice involves in vitro or cell-based systems which can provide mechanistic insights useful for screening type studies. However, these simplified models cannot fully predict the overall impact of drug transporter interaction on the PK properties of a drug. Single transporter knockout rats serve as more specific, definitive tools for predictive ADMET studies.

Typical study design includes:
  • n = 4 transporter knockout rats from one of SAGE® Labs ADMET 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 hrs post-dose
  • LC-MS/MS method development and qualification for the test article
  • Processing and analysis of plasma/CSF samples and dosing solutions
  • Expert Pharmacokinetics analysis and reporting
  • Alternatively, blood/plasma/CSF samples can be shipped back to the sponsor for analysis within 5 days of dosing
Influence of P-gp on quinidine CSF concentration

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.