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.

Regional Distribution of Peptide YY Concentrations in Human Lower Gastrointestinal Mucosa

PURPOSE: Peptide YY is composed of 36 amino acids, and its functions are suppression of gastric acid secretion, delay of gastric emptying, increase of intestinal motility, inhibition of pancreatic exocrine secretion, and enhanced postprandial colonic absorption of water and electrolyte. PYY is released from PYY cells, which are mainly distributed in the ileum and colon, in response to the presence of intraluminal lipids. This study was designed to determine the regional distribution of PYY in the normal human ileum, colon, rectum, and anal canal by studying mucosal concentrations. METHODS: Fresh tissues were obtained from specimens of segmental resections of the small bowel, colectomies, ileostomies, and abdominoperineal resections for the management of colonic or rectal carcinomas or benign diseases of the bowel. Only specimens devoid of advanced luminal obstruction were included. Mucosa was separately recruited by microdissection of frozen sections. Radioimmunoassays were performed using the methods of Adrian et al. RESULTS: The concentration of PYY was highest at 25 cm proximal to the ileocecal valve in the ileum (307.6 pmol/ g) and in the upper rectum at the colon (653.1 pmol/g). The concentration of PYY was 27.3 pmol/g in the anal canal distal to the dentate line. A clear differential distribution of PYY was shown in the ileum and colon. CONCLUSIONS: This study showed PYY was present in large amounts in the mucosa of the ileum and colon, with high concentrations in locations 25 cm proximal to ileocecal valve and in the upper rectum, respectively. The trend of regional differences in PYY in the colonic mucosa probably reflects local differences in functions, such as absorption and storage. Also, the peak concentration in the ileum at 25 cm proximal to ileocecel valve suggests that this region is the most abundant production site of PYY in the ileum.

The Distribution and Concentration of Ofloxacin Contained in Sustained Releasing Microsphere after Intraprostatic Injection / 대한비뇨기과학회지

PURPOSE: Sporadic excellent treatment results of intra-prostatic antibiotic injections against resistant chronic prostatitis were reported without sufficient background. So, for the scientific base of this effective treatment modality, we studied the tissue distribution and concentration of the ofloxacin after intraprostatic injection of formula which is designed for sustained release ofloxacin at least for four weeks. MATERIAL AND METHODS: 28 male dogs aged over 2 and ofloxacin designed to release over four weeks were used. The ofloxacin 12mg and poly(D,L-lactic) acid 28mg were prepared for sustained releasing formula and resolved in 1ml of 1.5% sodium carboxymethyl cellulose solution. Dogs were grouped into two, 8 control and 16 experiments for open injection. For control, oral ofloxacin 100mg was given twice a day for two and four weeks and for experimental groups, the new formula were injected at right lobe of prostate directly. The ofloxacin concentration was measured by high performance liquid chromatography(HPLC). RESULTS: Oral ofloxacin 2,800(2 weeks) and 5,600(4 weeks) were given for control and tissue concentration of ofloxacin were relatively even at all partitions of the prostate, 7.4+/-1.4(2 weeks) and 9.2+/-1.3mg/ml(4 weeks) and the blood level were 3.6-5.1mg/ml. In experimental groups, the only 12mg of ofloxacin was given and tissue concentration were 10.5+/-3.0(1 weeks), 13.8+/-4.5(2 weeks), 7.1+/-0.9(3 weeks) and 7.7+/-3.0mg/ml(4 weeks) in rights and 8.0+/-1.1(1 weeks), 10.2+/-4.2(2 weeks), 5.1+/-1.4(3 weeks) and 7.6+/-0.8(4 weeks)mg/ml in left lobes suggesting communication of blood between two lobes, and blood concentration were 0.16-0.59mg/ml. In histologic examination, the formula were localized between stroma and their size were reduced with time. CONCLUSIONS: Authors conclude that there are free communication of blood between two lobes of prostate and one direct injection of this sustained releasing formula ofloxacin into prostate can be a substitute with local effects without disturbing prostatic tissue level which reducing number or medication in future.

Comparison of Penetration Capability of Levofloxacin and Ciprofloxacin into Prostatic Tissue / 대한비뇨기과학회지

PURPOSE: To evaluate the penetration capability of Levofloxacin and Ciprofloxacin into prostatic tissue, we analysed the concentration of each drug in serum and prostatic tissue simultaneously after oral administration. MATERIALS AND METHODS: Eleven patients with benign prostatic hyperplasia treated with transurethral resection of the prostate were entered in this study. A single dose of 200mg Levofloxacin(LVFX) and 250mg ciprofloxacin(CPFX) were administered orally. Two hours after administration, blood and prostatic tissue samples were taken during operation. Concentration of each drug in serum and prostatic tissue was measured simultaneously by high performance liquid chromatography. RESULTS: The mean concentration of LVFX in serum was 1.970 +/- 0.759 microgram/ml, which was significantly higher than that of CPFX(0.903 +/- 0.291 microgram /ml)(p < 0.05). The mean concentration of LVFX in prostatic tissue(2.256 +/- 1.121 microgram/g), however, was not significantly different from that of CPFX(2.395 +/- 0.846 microgram/g). And the concentration ratio(tissue/serum concentration) of LVFX and CPFX was 1.16 and 2.76, respectively. CONCLUSIONS: These results show that LVFX is not superior to CPFX with respect to the penetration capability into prostatic tissue. Considering that the concentration of LVFX in prostatic tissue was higher than that in serum and not different from that of CPH, LVFX may be another potential effective agent in treating patients with chronic bacterial prostatitis.