Metabolism and Pharmacokinetics of Novel Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitor Apatinib in Humans

ABSTRACT Apatinib is a new oral antiangiogenic molecule that inhibits vascular endothelial growth factor receptor-2. The present study aimed to determine the metabolism, pharmacokinetics, and excretion of apatinib in humans and to identify the enzymes responsible for its metabolism. The primary routes of apatinib biotransformation included E-and Z-cyclopentyl-3-hydroxylation, N-dealkylation, pyridyl-25-N-oxidation, 16-hydroxylation, dioxygenation, and O-glucuronidation after 3-hydroxylation. Nine major metabolites were confirmed by comparison with reference standards. The total recovery of the administered dose was 76.8% within 96 hours postdose, with 69.8 and 7.02% of the administered dose excreted in feces and urine, respectively. About 59.0% of the administered dose was excreted unchanged via feces. Unchanged apatinib was detected in negligible quantities in urine, indicating that systemically available apatinib was extensively metabolized. The major circulating metabolite was the pharmacologically inactive E-3-hydroxy-apatinib-O-glucuronide (M9-2), the steady-state exposure of which was 125% that of the apatinib. The steady-state exposures of E-3-hydroxy-apatinib (M1-1), Z-3-hydroxy-apatinib (M1-2), and apatinib-25-N-oxide (M1-6) were 56, 22, and 32% of parent drug exposure, respectively. Calculated as pharmacological activity index values, the contribution of M1-1 to the pharmacology of the drug was 5.42 to 19.3% that of the parent drug. The contribution of M1-2 and M1-6 to the pharmacology of the drug was less than 1%. Therefore, apatinib was a major contributor to the overall pharmacological activity in humans. Apatinib was metabolized primarily by CYP3A4/ 5 and, to a lesser extent, by CYP2D6, CYP2C9, and CYP2E1. UGT2B7 was the main enzyme responsible for M9-2 formation. Both UGT1A4 and UGT2B7 were responsible for Z-3-hydroxyapatinib-O-glucuronide (M9-1) formation

An Emergency Decision-Making Method for Urban Rainstorm Water-Logging: A China Study

With the rapid development of the urbanization process, rainstorm water-logging events occur more frequently in big cities in China, which causes great impact on urban traffic safety and brings about severe economic losses. Water-logging has become a hot issue of widespread concern in China. As one kind of natural disasters and emergencies, rainstorm water-logging has the uncertainties of occurrence, development, and evolution. Thus, the emergency decision-making in rainstorm water-logging should be carried out in stages according to its development trend, which is very complicated. In this paper, an emergency decision-making method was proposed for urban water-logging with a hybrid use of dynamic network game technology, Bayesian analysis, and multi-attribute utility theory. The dynamic game process between “rainstorm water-logging” and “decision-making group” was established and the dynamic generation of emergency schemes was analyzed based on Bayesian analysis in various stages of water-logging. In terms of decision-making attributes, this paper mainly considered two goals, i.e., ensuring smooth traffic and controlling emergency cost. The multi-attribute utility theory was used to select the final scheme. An example analysis in Guangzhou of China showed that the method is more targeted and can achieve emergency management objectives more effectively when compared with traditional methods. Therefore, it can provide reference for the scientific decision-making of emergency management in urban rainstorm water-logging