Religious first- teachers second': Catholic elementary schooling in nineteenth-century South Australia

We studied if the clinical pharmacokinetics and drug-drug interactions (DDIs) of the sulfonylurea-derivative glibenclamide can be simulated via a physiologically-based pharmacokinetic modeling approach. To this end, a glibenclamide PBPK-model was build in Simcyp using in vitro physicochemical and biotransformation data of the drug, and was subsequently optimized using plasma disappearance data observed after i.v. administration. The model was validated against data observed after glibenclamide oral dosing, including DDIs. We found that glibenclamide pharmacokinetics could be adequately modeled if next to CYP metabolism an active hepatic uptake process was assumed. This hepatic uptake process was subsequently included in the model in a non-mechanistic manner. After an oral dose of 0.875 mg predicted Cmax and AUC were 39.7 (95% CI:37.0-42.7)ng/mL and 108 (95% CI: 96.9-120)ng/mLh, respectively, which is in line with observed values of 43.6 (95% CI: 37.7-49.5)ng/mL and 133 (95% CI: 107-159)ng/mLh. For a 1.75 mg oral dose, the predicted and observed values were 82.5 (95% CI:76.6-88.9)ng/mL vs 91.1 (95% CI: 67.9-115.9) for Cmax and 224 (95% CI: 202-248) vs 324 (95% CI: 197-451)ng/mLh for AUC, respectively. The model correctly predicted a decrease in exposure after rifampicin pre-treatment. An increase in glibenclamide exposure after clarithromycin co-treatment was predicted, but the magnitude of the effect was underestimated because part of this DDI is the result of an interaction at the transporter level. Finally, the effects of glibenclamide and fluconazol co-administration were simulated. Our simulations indicated that co-administration of this potent CYP450 inhibitor will profoundly increase glibenclamide exposure, which is in line with clinical observations linking the glibenclamide-fluconazol combination to an increased risk of hypoglycemia. In conclusion, glibenclamide pharmacokinetics and its CYP-mediated DDIs can be simulated via PBPK-modeling. In addition, our data underline the relevance of modeling transporters on a full mechanistic level to further improve pharmacokinetic and DDI predictions of this sulfonylurea-derivative

Interaction of fluvastatin with the liver-specific Na(+)-dependent taurocholate cotransporting polypeptide (NTCP)

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Dawn maps the surface composition of Vesta

By 7-October-2011, the Dawn mission will have completed Survey orbit and commenced high altitude mapping of 4Vesta. We present a preliminary analysis of data acquired by Dawn’s Framing Camera (FC) and the Visual and InfraRed Spectrometer (VIR) to map mineralogy and surface temperature, and to detect and quantify surficial OH. The radiometric calibration of VIR and FC is described. Background counting data acquired by GRaND are used to determine elemental detection limits from measurements at low altitude, which will commence in November. Geochemical models used in the interpretation of the data are described. Thermal properties, mineral-, and geochemical-data are combined to provide constraints on Vesta’s formation and thermal evolution, the delivery of exogenic materials, space weathering processes, and the origin of the howardite, eucrite, and diogenite (HED) meteorites