Pharmacokinetics, tissue distribution and excretion of QO-83, a novel KCNQ channel opener

AimTo establish a quantification method for compound QO-83 in rat biological matrices based on ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)and to explore its pharmacokinetic, tissue distribution, and excretion characteristics in vivo.MethodsFollowing CFDA guidelines, chromatographic and mass spectrometric conditions were optimized, and methodological parameters were validated. Through intravenous injection and intragastric administration in rats, blood drug concentration-time curves, tissue drug concentrations, and parent drug content in excreta were determined.ResultsMethodological validation indicated that the linearity, precision, accuracy, extraction recovery, matrix effect, and stability of compound QO-83 in plasma, tissue homogenates, and excreta matrix met requirements. Following intravenous and high/low dose intragastric administration of QO-83, the Cmax values were 1 196.3, 147.67, and 49.22 μg∙L-1 respectively, with corresponding AUC(0-t) values of 1 099.9, 680.12, and 217.02 μg∙h-1∙L-1, a half-life of 2.48 hours, and absolute bioavailability of 5.06%. Tissue distribution revealed detectable drug concentrations ranging from 54.93 to 747.33 ng∙g-1 in various tissues 15 minutes after intragastric administration, with concentrations ranging from 2.64 to 534.75 ng∙g-1 (excluding stomach tissue) 8 hours later; blood-brain drug concentration ratios were all above 100% at different time points. In excretion studies, the cumulative excretion rate in feces was 56.56%, in bile 0.067%, and no parent drug was detected in urine.ConclusionsThe developed method is sensitive, reliable, and efficient. While oral absorption of QO-83 is poor, its central distribution is significant. Further optimization of formulations or metabolism studies is needed to enhance its therapeutic efficacy.