UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a key role in detoxification of many potentially harmful compounds and drugs. UGT1A1 inhibition may bring risks of drug–drug interactions (DDIs), hyperbilirubinemia and drug-induced liver injury. This study aimed to investigate and compare the inhibitory effects of icotinib and erlotinib against UGT1A1, as well as to evaluate their potential DDI risks via UGT1A1 inhibition. The results demonstrated that both icotinib and erlotinib are UGT1A1 inhibitors, but the inhibitory effect of icotinib on UGT1A1 is weaker than that of erlotinib. The IC50 values of icotinib and erlotinib against UGT1A1-mediated NCHN-O-glucuronidation in human liver microsomes (HLMs) were 5.15 and 0.68 μmol/L, respectively. Inhibition kinetic analyses demonstrated that both icotinib and erlotinib were non-competitive inhibitors against UGT1A1-mediated glucuronidation of NCHN in HLMs, with the Ki values of 8.55 and 1.23 μmol/L, respectively. Furthermore, their potential DDI risks via UGT1A1 inhibition were quantitatively predicted by the ratio of the areas under the concentration–time curve (AUC) of NCHN. These findings are helpful for the medicinal chemists to design and develop next generation tyrosine kinase inhibitors with improved safety, as well as to guide reasonable applications of icotinib and erlotinib in clinic, especially for avoiding their potential DDI risks via UGT1A1 inhibition.

Our pharmacokinetics of oxycodone injection in Chinese patients with pain strongly support continued development of oxycodone as an effective analgesic drug in China.

This single-center, observational study analyzed the association between plasma concentration of sorafenib and its safety and efficacy in Chinese patients with metastatic renal cell carcinoma (mRCC). Adult patients with RCC (n = 94), treated with sorafenib were enrolled between January 2014 and January 2015. Sorafenib plasma concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety and efficacy variables were evaluated using National Cancer Institute-Common Toxicity Criteria for Adverse Events and Response Evaluation Criteria in Solid Tumors criteria. Association of plasma concentration with safety and efficacy was analyzed. The steady state plasma concentration of sorafenib after 2 weeks of treatment ranged from 881 to 12,526 ng/mL. Major adverse reactions (ADRs) included diarrhea (76.5%), hand-foot syndrome (HFS; 68.99%) and fatigue (55.32%). Significant association was reported between plasma concentration and all the ADRs except rash. At 6 weeks, complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) was reported in 3.1%, 13.82%, 52.2% and 13.82% patients, respectively. Objective response and disease control rates were 17.02% and 69.14%. Plasma concentration of sorafenib was >10,000 ng/mL in patients with severe ADRs, which decreased with reduction in dose or discontinuation of treatment. After 21.2 weeks follow-up, median progression free survival was 12.3 months. CR, PR, SD and PD were reported in 1%, 46%, 33% and 19% patients. In conclusion, plasma concentration of sorafenib was associated with its safety and efficacy in Chinese patients with mRCC.

1.Endogenous compounds have been reported to be the regulators of UDP-glucuronosyltransferases (UGTs) isoforms. This study aims to investigate the regulatory effects of the activity of UGT isoforms by two important lipid components phosphatidylcholine (PC) and lysophosphatidylcholines (LPC) using in vitro incubation system. 2.UGTs supersomes-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as the probe reaction to evaluate the inhibition of compounds towards UGT isoforms except UGT1A4, and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reaction was utilized to phenotype the activity of UGT1A4. 3.About 50 μM of LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0 exhibited inhibition towards more than 90% activity of UGT isoforms, and other LPC and PC components showed negligible inhibitory potential towards all the UGT isoforms. UGT1A6 and UGT1A8 were identified to be the most sensitive UGT isoforms susceptible for the inhibition by LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0, indicating the strong influence of these LPC and PC components towards UGT1A6 and UGT1A8-catalyzed metabolic reaction when the concentrations of these components increased.