Application Of Physiologically Based Pharmacokinetic Models For Assessing The Disposition Of Promethazine In Simulated Weightless Rats

Classical compartmental models are usually used in the study on pharmacokinetics in space, they are very poor for physiological interpretation. It is difficult to predict kinetic profiles when the underlying physiology changes in weightlessness,which can make astronauts in potential dangers. Physiological based pharmacokinetic(PBPK) models can describe drug disposition based on the physiological parameters and physiochemical properties. This project is the first application of PBPK models in the pharmacokinetic study under simulated weightlessness. The PBPK models of rats under ambulatory and tail-suspended condition are established. The project aims to build the individual administration schemes for astronauts based on the extrapolation of dosage and routes of administration from rat in normal gravity to rat in simulated weightlessness. At last, the extrapolations from rat to human are realized. We endeavor in making beneficial discover of drug research in space to ensure the drug for astronauts safe and effective.1 The establishment of the LC-MS/MS methods for promethazine(PMZ) and promethazine sulphoxide(PMZSO) in rat plasma, tissues, urine and fecesSensitive and simple LC-MS/MS methods for quantitative determination of PMZ and PMZSO in rat plasma, heart, liver, kidney, brain, muscle, urine and feces were developed. All values of accuracy, precision and recovery were within the recommended limits.2 Pharmacokinetic study of PMZ and PMZSO in normal and simulated weightless rat plasmaThe concentration of PMZ in normal and simulated weightless rat plasma was determined at different time after oral administration at the dose of 4.5 mg/kg, 9.0 mg/kg and 18 mg/kg PMZ. Pharmacokinetic parameters were attained by DAS 2.0. The results indicated that PMZ follows linear plasma pharmacokinetics in normal and simulated weightless rats across the investigated dosage range(4.5–18 mg/kg). AUC of PMZ in simulated weightless rats following thress dosages are smaller than those in normal rats, and AUC of PMZSO in simulated weightless rats following 9.0 mg/kg PMZ is bigger than that in normal rats, which indicates that more PMZ is metabolized to PMZSO in simulated weightless rats.3 The study of tissue distribution of PMZ and PMZSO in normal and simulated weightless ratsAfter administration of 9 mg/kg PMZ to normal and simulated weightless rats, the concentrations of PMZ in main tissues were as follows: heart > brain > muscle >liver > kidney, and the concentrations of PMZSO in main tissues were as follows: liver > heart > brain > muscle > kidney. In addition, more PMZ distributes in normal rat brain, liver, kidney and muscle and less PMZ distributes in normal rat heart than that in simulated weightless rat tissues. And less PMZSO distributes in normal rat heart, brain, liver, kidney and muscle than that in simulated weightless rat tissues.4 The study of excretion of PMZ in in normal and simulated weightless ratsPMZ was given to the normal and simulated weightless rats by gastrogavage at the dose of 9.0 mg/kg. The ratios of PMZ and PMZSO in normal rat urine were 0.8 % and 3.8 % of the total and the ratios of those in normal rat feces was were 0.2 % and 0.16 %of the total. In addition, the ratios of PMZ and PMZSO in simulated weightless rat urine were 0.77 % and 3.6 % of the total and the ratios of those in simulated weightless rat feces was were 0.2 % and 0.15 % of the total.5 The study of CYP2D6 expression in normal and simulated weightless ratsWestern blot analysis indicated that CYP2D6 protein was expressed in livers of all simulated weightless rats as well as control group rats. The expression of CYP2D6 in simulated weightless rat liver was significantly upregulated in the early stage(3 days and 7 days suspension groups) compared with control group(P < 0.05). The level of CYP2D6 expression appeared peak at 7 days, followed by a declining and steady tendency(15 days and 30 days), which were still significantly higher than the level of the control group.6 PBPK model establishment of PMZ in normal and simulated weightless rats and extrapolations from rat to humanA flow-limited, PBPK model for useinestimating of PMZ in normal and simulated weightless rats was developed. Concentration data in normal and simulated weightless plasma and tissues gained from experiments measurement and those gained from PBPK model were compared in order to test and verify the effectiveness of the model. And At last, the extrapolations from rat to human are realized. We endeavor in making beneficial discover of drug research in space to ensure the drug for astronauts safe and effective.