Physiologically based pharmacokinetic modeling of the inhibitory effect of dapagliflozin on intestinal and renal SGLT / 药学学报

This study establishes and optimizes the physiologically based pharmacokinetics (PBPK) model for dapagliflozin, predicts the drug distribution into relevant tissues, and calculates the inhibitory effect on the sodium-glucose cotransporters (SGLTs) in the intestine and renal proximal tubule. Based on literature data, a PBPK model for oral administration in healthy adults was established and the predicted blood concentration-time curve characteristics, the main pharmacokinetic parameters (PK), and drug excretion in urine were compared with the published data. To verify and optimize the model and verify the accuracy of the tissue distribution and concentration predictions, a pharmacodynamics model (PD) was established. Urine glucose excretion (UGE) was simulated at the corresponding times. The characteristics of the drug-time curve predicted by the model are similar to those of the measured curve, and the ratio of the main PK parameters to the measured values is within a two-fold range; the accuracy of the established PBPK model is good. The maximal inhibition obtained with 10 mg of dapagliflozin on the duodenum and jejunum segment sodium-glucose co-transporter 1 (SGLT1s) was 1.6%-4.7%, and the inhibition rate of the sodium-glucose co-transporter 2 (SGLT2s) in the proximal tubule of the kidney was as high as 99.9%. At a dose of 10 mg, dapagliflozin delayed intestinal glucose absorption while occupying most of the sites (99.9%) of the renal sodium-glucose cotransporter 2 and inhibiting its glucose reabsorption. This physiological-pharmacokinetic model for dapagliflozin in healthy adults can provide meaningful guidance for exploring pharmacological mechanisms and potential toxicity of gliflozin by simulating drug distribution in different tissues.

Proton Transfer Reaction Time-of-Flight Mass Spectrometry for Detection of Trace Volatile Organic Compounds in Breath / 分析化学

Based on the modification of inlet of a proton transfer reaction time of flight mass spectrometry ( PTR-TOF-MS) instrument developed in our laboratory, a new method for real-time and on-line quantitation of volatile organic compounds ( VOCs) from human exhalation was established. A 28-day real-time and on-line monitoring of exhaled breath from 23 volunteers (11 male healthy subjects, 11 female healthy subjects and 1 stomach-sick patient) was carried out and the experimental results showed that the major potential VOCs markers were identified as formaldehyde, propylene, acetone, acetaldehyde, isopropanol and isoprene, and their concentrations obeyed the Normal Distribution. The concentrations of formaldehyde, propylene and isopropanol were mainly in the range of 40 to 100 ppb, acetaldehyde in the range of 80 to 180 ppb, acetone in the range of 500 to 1500 ppb, and isoprene in the range of 8 to 20 ppb. Meanwhile, the concentrations for some compounds were different for men and women. Men have higher level of acetone, and women have higher levels of acetaldehyde and isopropanol. In addition, the concentrations of formaldehyde and acetone in the exhaled breath of stomach sicknesses were significantly higher than that in healthy people. Ethanol and acetaldehyde were the main potential markers of exhale breath after drinking alcohol. The acetaldehyde was the major metabolite of ethanol, and the concentration of acetaldehyde changed with the concentration variation of ethanol in degradation process.

Hemodynamic characteristics of arterial lesions after drug-eluting stent implantation / 医用生物力学

Objective To study the hemodynamic characteristics after vascular drug eluting stent (DES) implantation, so as to provide theoretical guidance for clinical application of DES as well as improving the design of DES. Methods The geometry models of vascular lesions implanted with DES were constructed to numerically analyze drug concentration and wall shear stress (WSS) distributions in vessel by computational fluid dynamics (CFD) method. The results were compared with flow characteristics of the model with bare metal stent (BMS) implantation. Results Low WSS accompanied by high drug concentration would occur during blood flow in some areas after DES implantation, and vice versa. The presence of DES significantly reduced appearing such areas as either with low WSS only or with low drug concentration only. Theoretically, DES had more advantages than BMS at the stage of drug release. Conclusions DES could dramatically reduce the ratio of in-stent restenosis. Understanding the regular pattern of blood flow field distributions after DES implantation in detail will be beneficial to improve the design of DES, and further advance the overall performance of the stent, which can provide the theoretical basis for clinical research.