Correlation of pharmacokinetic features and tissue distribution with toxicity of Q39, a hypoxic cell cytotoxic agent.

3-(4-Bromophenyl)-2-(ethylsulfonyl)-6-methyl- quinoxaline 1,4-dioxide (Q39), is one of synthesized tirapazamine (TPZ) analogues that has been investigated preclinically as a hypoxic anticancer candidate. To date, there has not been a study to systematically evaluate the toxicity and pharmacokinetics of Q39. In the present study, we characterized the toxicity profile of Q39 in ICR mice. No toxicities were observed in mice treated with Q39 at dose levels that 168 mg/kg. LD 50 value was 257.8 mg/kg (95% confidence interval = 231.1-287.5 mg/kg), which was 3.3-fold higher than that of TPZ. For the plasma pharmacokinetic assessment, a balb/c nude mice bearing K562 leukemia cell xenografted model was introduced and dosed with Q39 intravenous (i. v.)(1.0 mg/kg). Rapid resolution liquid chromatography coupled with tanderm mass spectrometry quantitative detection method (RRLC-MS/MS) was used to quantitatively determine plasma concentration. The RRLC-MS/MS method was validated within the concentration range 25-2000 ng/mL, and the calibration curves were linear with correlation coefficients of >0.999. Following intravenous administration to nude mice (1.0 mg/kg), plasma concentrations declined rapidly from 1063.3 μg/mL at 10 min to 81.5 μg/mL at 3 h. Elimination was triexponential, with T 1/2 values of 1.4 h. The CL was 930.0 mUh/kg, the V d was 1.88 Ukg, and the AUC 0-∞ was 1080.5 ng/mL h. In the tissue distribution assay, concentration of Q39 was higher in the heart, liver, spleen and tumor tissues. The present study offers insights into the toxicological and pharmacologic profiles of Q39 which could help to optimize the dosage of Q39 for the future research and development.