Abstract
Our 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.
Original language | English (US) |
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Article number | e1173 |
Journal | Pharmacology Research and Perspectives |
Volume | 12 |
Issue number | 1 |
DOIs | |
State | Published - Feb 2024 |
Bibliographical note
Publisher Copyright:© 2024 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
Keywords
- 2-deoxyglucose
- drug–drug interaction
- hydroxychloroquine
- oral drug–drug PK interference
PubMed: MeSH publication types
- Journal Article