bcrp - publications

Predict more bcrp - ligand interactions now!



Characterization of SAGE Mdr1a (P-gp), Bcrp, and Mrp2 Knockout Rats Using Loperamide, Paclitaxel, Sulfasalazine, and Carboxydichlorofluorescein Pharmacokinetics.


Drug Metab Dispos. 2012 Jun 18;


Authors: Zamek-Gliszczynski MJ, Bedwell DW, Bao JQ, Higgins JW


Abstract

Transporter gene knockout rats are practically advantageous over murine models for pharmacokinetic and excretion studies, but their phenotypic characterization is lacking. At present, relevant aspects of pharmacokinetics, metabolism, distribution, and excretion of transporter probes (P-gp: loperamide and paclitaxel, Bcrp: sulfasalazine, Mrp2: carboxydichlorofluorescein) were studied systematically across SAGE Mdr1a-, Bcrp-, and Mrp2-knockout rats. In Mdr1a-knockout rats, loperamide and paclitaxel oral bioavailability was 2- and 4-fold increased, respectively, while clearance was significantly reduced (40-42%), consistent with the expected 10-20-fold reduction in paclitaxel excretion. N-desmethyl-loperamide pharmacokinetics were not altered in all three knockouts following oral loperamide. In rats lacking P-gp, paclitaxel brain partitioning was significantly increased (4 fold). This finding is consistent with observations of loperamide CNS opioid pharmacology in Mdr1a-knockout rats. Sulfasalazine oral bioavailability was markedly increased 21 fold in Bcrp knockouts, and as expected, was also 2-3-fold higher in P-gp- and Mrp2-knockout rats. The sulfapyridine metabolite-to-parent ratio was decreased 10 fold in rats lacking Bcrp following oral, but not intravenous, sulfasalazine administration. Carboxydichlorofluorescein biliary excretion was obliterated in Mrp2-knockout rats, resulting in 25% decreased systemic clearance and 35% increased half-life. In contrast, carboxydichlorofluorescein renal clearance was not impaired in the absence of Mrp2, Bcrp, or P-gp. In conclusion, SAGE Mdr1a-, Bcrp-, and Mrp2-knockout rats generally demonstrated the expected phenotypes with respect to alterations in pharmacokinetics of relevant probe substrates; therefore, these knockout rats can be used as an alternative to murine models whenever a larger species is practically advantageous or more relevant to the drug discovery/development program.

PMID: 22711747 [PubMed - as supplied by publisher]