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

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

Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities

Abstract: Tanshinones are a class of abietane diterpene compound isolated from Salvia miltiorrhiza (Danshen or Tanshen in Chinese), a well-known herb in Traditional Chinese Medicine (TCM). Since they were first identified in the 1930s, more than 40 lipophilic tanshinones and structurally related compounds have been isolated from Danshen. In recent decades, numerous studies have been conducted to investigate the isolation, identification, synthesis and pharmacology of tanshinones. In addition to the well-studied cardiovascular activities, tanshinones have been investigated more recently for their anti-cancer activities in vitro and in vivo. In this review, we update the herbal and alternative sources of tanshinones, and the pharmacokinetics of selected tanshinones. We discuss anti-cancer properties and identify critical issues for future research. Whereas previous studies have suggested anti-cancer potential of tanshinones affecting multiple cellular processes and molecular targets in cell culture models, data from in vivo potency assessment experiments in preclinical models vary greatly due to lack of uniformity of solvent vehicles and routes of administration. Chemical modifications and novel formulations had been made to address the poor oral bioavailability of tanshinones. So far

Single Oral Dose Pharmacokinetics of Decursin and Decursinol Angelate in Healthy Adult Men and Women

<div><p>The ethanol extract of <i>Angelica gigas</i> Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our <i>in vitro</i> metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (<i>T_max</i>) of 2.1, 2.4 and 3.3 h and mean peak concentration (<i>C_max</i>) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (<i>t_1/2</i>) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC_0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h∙nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02114957" target="_blank">NCT02114957</a></p></div

CONSORT flow diagram for single dose PK study of Cogni.Q pyranocoumarins.

<p>CONSORT flow diagram for single dose PK study of Cogni.Q pyranocoumarins.</p

Human plasma concentration (Cp)-time profiles of pyranocoumarins after a single oral dose of Cogni.Q.

<p>(a) Parent compounds D and DA. (b) Product DOH. Mean ± SEM of all 20 subjects. Inserts show the semi-log plot of Cp versus time for corresponding analytes. Terminal <i>t</i>_<i>1/2</i> for D and DA was statistically the same (17.4 and 19.3 hours, respectively) and that for DOH was shorter (7.4 hours).</p