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.

Metabolomic investigate into the serum of pulmonary hypertension Beagle dogs and the effect of sGC003 / 药学学报

Based on dehydrogenation of monocrotaline-induced Beagle dog model of pulmonary hypertension (PH), GC-TOF-MS metabolomics technique was used to identify potential biomarkers and biologically significant changes in the serum. Pattern recognition method was used for processing metabolomics data to compare PH Beagle dogs (n=11) versus healthy controls (n=8). The results show that 514 compounds were detected in the serum. The profiles of PH models and healthy controls can be distinguished clearly, indicating that there are significant differences in the metabolic profiles. Data analysis revealed 15 types of potential biomarkers, including amino acids glycine and 3-cyanoalanine, glucose, fructose, 1-monopalmitic acid glycerin, and malic acid. Diversified metabolites and their metabolic pathways have been analyzed. We found that different degrees of turbulence and disorganization occurred in glyoxylate and dicarboxylate metabolism, TCA cycle, starch and sucrose metabolism pathways in the Beagle dogs. A soluble guanylate cyclase activator, 4,6-diamino-2-[1-(3-fluorothiophen-2-yl)methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl-N-methyl methyl carbamate (sGC003), was administered (n=15) for comparison with the model and the control. We found that three groups were clearly clustered, indicating that there were differences in the three groups of metabolites. ANOVA statistical analysis results suggested that sGC003 exhibited pharmacodynamic effect, and at the same time, it also changed the endogenous metabolites to some extent. This study laid a foundation for the application of metabolomics in early diagnosis of pulmonary hypertension and provided experimental evidence for the application of sGC003 compound. In this study, the program of animal testing had been approved by Committee on the management of experimental animal in the Beijing Rixin Technology Co. Ltd.

Study on bioequivalence of domestic bambuterol capsules and imported tablets by high performance capillary zone electrophoresis / 药学学报

<p><b>AIM</b>To study bioequivalences of bambuterol and its metabolites terbutaline in 20 healthy male volunteers.</p><p><b>METHODS</b>A single oral dose of domestic bambuterol capsule or imported bambuterol tablet was given according to a randomized 2-way cross-over design. The plasma bambuterol and terbutaline concentrations were determined by high performance capillary zone electrophoresis (HPCZE).</p><p><b>RESULTS</b>The pharmacokinetic parameters of the capsule and tablet of bambuterol: AUC0-1 were (72 +/- 18) and (72 +/- 13) microgram.h.L-1, Cmax were (8.1 +/- 1.8) and (9.2 +/- 2.3) microgram.L-1, Tmax were (3.6 +/- 1.3) and (3.7 +/- 1.0) h, respectively; terbutaline: AUC0-t were (129 +/- 32) and (130 +/- 34) microgram.h.L-1, Cmax were (7.8 +/- 2.2) and (8.5 +/- 2.9) microgram.L-1, Tmax were (5.4 +/- 0.8) and (5.6 +/- 1.1) h, respectively. The bioavaiability of the capsule was (100 +/- 16)% (bambuterol) and (101 +/- 13)% (terbutaline).</p><p><b>CONCLUSION</b>The results demonstrated that the two preparations of bambuterol and terbutaline were bioequivalent by analysis of variance, with two-one sided test at 90% confidential level.</p>