Optimization of dose and route of administration of the P‐glycoprotein inhibitor, valspodar (PSC‐833) and the P‐glycoprotein and breast cancer resistance protein dual‐inhibitor, elacridar (GF120918) as dual infusion in rats

Abstract

Transporters can play a key role in the absorption, distribution, metabolism, and excretion of drugs. Understanding these contributions early in drug discovery allows for more accurate projection of the clinical pharmacokinetics. One method to assess the impact of transporters in vivo involves co‐dosing specific inhibitors. The objective of the present study was to optimize the dose and route of administration of a P‐glycoprotein (P‐gp) inhibitor, valspodar (PSC833), and a dual P‐gp/breast cancer resistance protein (BCRP) inhibitor, elacridar (GF120918), by assessing the transporters’ impact on brain penetration and absorption. A dual‐infusion strategy was implemented to allow for flexibility with dose formulation. The chemical inhibitor was dosed intravenously via the femoral artery, and a cassette of known substrates was infused via the jugular vein. Valspodar or elacridar was administered as 4.5‐hour constant infusions over a range of doses. To assess the degree of inhibition, the resulting ratios of brain and plasma concentrations, Kp's, of the known substrates were compared to the vehicle control. These data demonstrated that doses greater than 0.9 mg/hr/kg valspodar and 8.9 mg/hr/kg elacridar were sufficient to inhibit P‐gp‐ and BCRP‐mediated efflux at the blood‐brain barrier in rats without any tolerability issues. Confirmation of BBB restriction by efflux transporters in preclinical species allows for subsequent prediction in humans based upon the proteomic expression at rodent and human BBB. Overall, the approach can also be applied to inhibition of efflux at other tissues (gut absorption, liver clearance) or can be extended to other transporters of interest using alternate inhibitors.

Construction and Functional Evaluation of a Three-Dimensional Blood–Brain Barrier Model Equipped With Human Induced Pluripotent Stem Cell-Derived Brain Microvascular Endothelial Cells

“…5c, d and Table II). In particular, a previous study in rats reported an efflux ratio of 4.2 for dantrolene and also found comparable expression of BCRP in human, rat, and mouse BBBs (41,42), supporting the results obtained in the present study. Furthermore, the efflux ratio value of cladribine was decreased to 1.45 in the presence of Ko143, a BCRP inhibitor (Table II), and the inhibition of BCRP enhanced the transport of cladribine in the A-to-B direction and lowered that in the B-to-A direction, indicating luminal localization of BCRP in hiPS-BMECs.…”

Discovery of Substituted Di(pyridin-2-yl)-1,2,4-thiadiazol-5-amines as Novel Macrofilaricidal Compounds for the Treatment of Human Filarial Infections

“…Having identified compounds with limited brain exposure, further profiling was needed to determine whether the inhibition of Pgp would be of consequence for further development. Compound 47 still maintained high permeability in the MDCK wild-type cell line treated with elacridar (a PgP and BCRP inhibitor), 31 47 P appA-B = 30 × 10 –6 cm/s. Compound 47 still maintained good oral exposure having slow plasma clearance in the mouse, 3.6 mL/min/kg.…”

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

“…This generation of inhibitors is created by structurally altering first-generation inhibitors in order to achieve low toxicity, high selectivity, and potency. Doxverapamil, dofequidarfumerate, biricodar citrate (VX710) [66], valspodar (PSC 833) [67], and dexniguldipine are examples of this generation of inhibitors. This group mostly includes non-immunosuppressive equivalents of doxverapamil as well as cyclosporine A [68].…”