2‐Deoxyglucose and hydroxychloroquine HPLC‐MS–MS analytical methods and pharmacokinetic interactions after oral co‐administration in male rats

Abstract

AbstractOur previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2‐deoxyglucose (2‐DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2‐addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS–MS) analytical methods for 2‐DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples. Using a jugular vein‐cannulated male rat model with serial blood collection before and after a single gavage dose of each drug alone or in combination, we examined their PK metrics for drug–drug interactions. The data demonstrated a rapid and complete separation of 2‐DG from common monosaccharides by HPLC‐MS–MS multi‐reaction monitoring. Application of the HPLC‐MS–MS 2‐DG and HCQ methods to sera samples of nine rats showed a peak time (Tmax) for 2‐DG of 0.5 h after 2‐DG alone or with HCQ and identical post‐peak half‐life of approximately 1 h. With a seemingly bi‐modal time course for HCQ, the Tmax for HCQ alone (1.2 h) was faster than that for the combination (2 h; p = .017). After combination dosing, the peak concentration (Cmax) and area under the curve (AUC0‐4h) of 2‐DG were decreased by 53.8% (p = .0004) and 53.7% (p = .0001), whereas AUC0‐8h for HCQ was decreased by 30.8% (p = .0279) from the respective single dosing. Without changing the mean residence time (MRT0‐∞) of each drug, the combination affected the apparent volume of distribution (Vd) and clearance (CL) of 2‐DG, and CL for HCQ without affecting its Vd. We observed significant negative PK interactions, probably at the intestinal absorption level, between 2‐DG and HCQ taken simultaneously by mouth. Future optimization efforts are warranted for their combination regimen for clinical translation.