Development of a sensitive UHPLC-MS/MS method for the pharmacokinetics study of a novel tyrosine kinase inhibitors, 1-[4-(4-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-phenyl)-piperazin-1-yl]-propenone in rats

Targeted inhibition of epidermal growth factor receptor has become an important means of chemotherapy for nonsmall cell lung cancer, breast cancer, pancreatic cancer, colon cancer and other malignant tumors. Although remarkable curative effects have been achieved in the past few decades, the emergence of drug resistance is a problem. Therefore, new inhibitors need to be developed. XHL-31 is a new candidate with significant inhibitory activity against T790M and C797S mutations in vitro. In order to study the pharmacokinetics in vivo, a sensitive and efficient UHPLC-MS/MS method was developed for the determination of XHL-31 in rat plasma in this study. The lower limit of quantitation of this method was 1 ng/ml and the linear range was 1-2,000 ng/ml. Method validation showed a high accuracy and precision, a high stability, a high recovery and repeatability. The method was successfully applied to the pharmacokinetic study of XHL-31 in rats. The results indicated that there were significant gender differences in oral absorption and the absolute bioavailability of XHL-31 in female rats were extremely low (<10%).

Automated summary

Targeted inhibition of epidermal growth factor receptor is important in chemotherapy for various malignant tumors. XHL-31, a new candidate, shows significant inhibitory activity against drug-resistant mutations. Gender differences in pharmacokinetics of XHL-31 were observed in rats.