Prediction of Human Pharmacokinetics of E0703, a Novel Radioprotective Agent, Using Physiologically Based Pharmacokinetic Modeling and an Interspecies Extrapolation Approach.

E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing radiation. In this study, we characterize its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. The preclinical PK of E0703 was studied in mice and Rhesus monkeys. Asian human clearance (CL) values for E0703 were predicted from various allometric methods. The human PK profiles of E0703 (30 mg) were predicted by the PBPK model in Gastro Plus software 9.8 (SimulationsPlus, Lancaster, CA, USA). Furthermore, tissue distribution and the human PK profiles of different administration dosages and forms were predicted. The 0.002 L/h of CL and 0.005 L of Vss in mice were calculated and optimized from observed PK data. The plasma exposure of E0703 was availably predicted by the CL using the simple allometry (SA) method. The plasma concentration-time profiles of other dosages (20 and 40 mg) and two oral administrations (30 mg) were well-fitted to the observed values. In addition, the PK profile of target organs for E0703 exhibited a higher peak concentration (Cmax) and AUC than plasma. The developed E0703-PBPK model, which is precisely applicable to multiple species, benefits from further clinical development to predict PK in humans.

Inflammation and coagulation abnormalities via the activation of the HMGB1­RAGE/NF­κB and F2/Rho pathways in lung injury induced by acute hypoxia.

High­altitude acute hypoxia is commonly associated with respiratory cardiovascular diseases. The inability to adapt to acute hypoxia may lead to cardiovascular dysfunction, lung injury and even death. Therefore, understanding the molecular basis of the adaptation to high­altitude acute hypoxia may reveal novel therapeutic approaches with which to counteract the detrimental consequences of hypoxia. In the present study, a high­altitude environment was simulated in a rat model in order to investigate the role of the high mobility group protein­1 (HMGB1)/receptor for advanced glycation end products (RAGE)/NF­κB and F2/Rho signaling pathways in lung injury induced by acute hypoxia. It was found that acute hypoxia caused inflammation through the HMGB1/RAGE/NF­κB pathway and coagulation dysfunction through the F2/Rho pathway, both of which may be key processes in acute hypoxia­induced lung injury. The present study provides new insight into the molecular basis of lung injury induced by acute hypoxia. The simultaneous activation of the HMGB1/RAGE/NF­κB and F2/Rho signaling pathways plays a critical role in hypoxia­induced inflammatory responses and coagulation abnormalities, and provides a theoretical basis for the development of potential therapeutic strategies.