TY - JOUR T1 - Ketamine pharmacokinetics and pharmacodynamics are altered by Pgp and Bcrp efflux transporters in mice JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.078360 SP - dmd.117.078360 AU - Samit Ganguly AU - John C Panetta AU - Jessica K Roberts AU - Erin G Schuetz Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/04/19/dmd.117.078360.abstract N2 - To understand the systemic impact of Bcrp and Pgp deletion, untargeted metabolomics was performed on CSF and plasma of wild-type (WT) and Pgp and Bcrp double knockout (dKO) rats anesthetized with ketamine-xylazine. We unexpectedly found elevated ketamine levels in both CSF and plasma of dKO versus WT rats. Therefore, the effect of these transporters was investigated on ketamine's (i) oral (PO) and intraperitoneal (IP) serum pharmacokinetics (PK), using a liquid chromatography (HPLC-UV) method, and (ii) anesthetic effect using a duration of loss of righting reflex (dLORR) test in WT, Bcrp KO, Pgp KO, and Pgp-Bcrp dKO mice. The PK data demonstrated a significantly increased oral bioavailability and serum exposure of ketamine in the dKO > Pgp KO > Bcrp KO compared to the WT mice. IP Ketamine-induced dLORR was significantly longer in the dKO > Pgp KO > Bcrp KO > WT mice compared to the WT mice. Inhibition of Bcrp and Pgp in WT mice using the dual Pgp/Bcrp inhibitor elacridar increased the ketamine-induced dLORR compared to the vehicle-treated mice. Ketamine intracellular concentration was significantly decreased in MDCKII BCRP/PGP cells compared to the parental cells. In total, these results demonstrate that ketamine appears to be a dual Pgp/Bcrp substrate whose pharmacokinetics and pharmacodynamics are affected by Pgp and Bcrp-mediated efflux. ER -