Advanced Satellite-Based Frequency Transfer at the 10-16 Level.

Advanced satellite-based frequency transfers by two-way carrier-phase (TWCP) and integer precise point positioning have been performed between the National Institute of Information and Communications Technology and Korea Research Institute of Standards and Science. We confirm that the disagreement between them is less than at an averaging time of several days. In addition, an overseas frequency ratio measurement of Sr and Yb optical lattice clocks was directly performed by TWCP. We achieved an uncertainty at the mid-10-16 level after a total measurement time of 12 h. The frequency ratio was consistent with the recently reported values within the uncertainty.

Population pharmacokinetics of a novel histone deacetylase inhibitor, cyclo{(2S)-2-amino-8-[(aminocarbonyl)hydrazono] decanoyl-1-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinecarbonyl} (SD-2007), and its metabolic conversion to apicidin after intravenous injection and oral administration in rats.

BACKGROUND: This study assessed the population pharmacokinetics and metabolic conversion of a novel histone deacetylase (HDAC) inhibitor, SD-2007, into its active metabolite, apicidin, in rats. METHODS: SD-2007 was given to rats by intravenous injection (4 mg/kg) and oral administration (40 mg/kg). Serum concentrations of SD-2007 and apicidin were determined by LC-MS/MS. All concentrations were analyzed using a population pharmacokinetic model with 9 compartments in S-ADAPT. RESULTS: The area under the curve for apicidin was 96 ± 16 mg·h/ml after 4 mg/kg administered intravenously and 2,455 ± 1,211 mg·h/ml after 40 mg/kg given orally. The population pharmacokinetic model described all profiles well. After oral administration of SD-2007, the median absolute bioavailability of SD-2007 was 6.67% (range 3.83-9.89) and the median apparent bioavailability was 22.3% (range 15.7-35.8) for apicidin, whereas only a median of 8.85% (range 7.57-9.34) of an intravenous SD-2007 dose was converted to apicidin. CONCLUSIONS: Oral SD-2007 displayed a substantial presystemic metabolism to active apicidin. The high serum concentrations of apicidin after oral administration of SD-2007 may cause significant HDAC inhibition.

Assessment of bisphenol A exposure in Korean pregnant women by physiologically based pharmacokinetic modeling.

The objective of this study was to predict the exposure to bisphenol A (BPA) after oral intake in human blood and tissues using physiologically based pharmacokinetic (PBPK) modeling. A refined PBPK model was developed taking into account of glucuronidation, biliary excretion, and slow absorption of BPA in order to describe the second peak of BPA observed following oral intake. This developed model adequately described the second peak and BPA concentrations in blood and various tissues in rats after oral administration. A prospective validation study in rats additionally supported the proposed model. For extrapolation to humans, a daily oral BPA dose of 0.237 mg/70 kg/d or 0.0034 mg/kg/d was predicted to achieve an average steady-state blood concentration of 0.0055 ng/ml (median blood BPA concentration in Korean pregnant women). This dose was lower than the reference dose (RfD, 0.016 mg/kg/d) and the tolerable daily intake established by the European Commission (10 µg/kg/d). Data indicate that enterohepatic recirculation may be toxicologically important as this pathway may increase exposure and terminal half-life of BPA in humans.

Determination of zearalenone by liquid chromatography/tandem mass spectrometry and application to a pharmacokinetic study.

Zearalenone, a mycotoxin biosynthesized by various Fusarium fungi, is widely found as a contaminant in grains and animal feeds. This study describes a rapid and sensitive LC/MS/MS assay method for the quantification of zearalenone in rat serum. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification (LLOQ), accuracy and precision. The multiple reaction monitoring was based on the transition of m/z 317.0 --> 130.9 for zearalenone and 319.0 --> 204.8 for zearalanone (internal standard). The assay utilized a single liquid-liquid extraction with t-butyl methyl ether and isocratic elution, and the LLOQ was 0.5 ng/mL using 0.1 mL rat serum. The assay was linear over a concentration range from 0.5 to 200 ng/mL, with correlation coefficients >0.9996. The mean intra- and inter-day assay accuracy was 101.2-112.9 and 96.3-108.0%, respectively. The mean intra- and inter-day precision was between 1.3-7.6 and 3.6-10.6%, respectively. The developed assay was applied to a pharmacokinetic study after a bolus intravenous injection of zearalenone in rats.

Prediction of drug bioavailability in humans using immobilized artificial membrane phosphatidylcholine column chromatography and in vitro hepatic metabolic clearance.

This study reports a rapid screening method for the prediction of oral drug bioavailability in humans based on combined immobilized artificial membrane (IAM) chromatographic capacity factor (k(IAM)) and in vitro stability in hepatic microsomes. The fraction of drug absorbed (F(a)) in humans was predicted for a set of 15 structurally diverse commercial drugs based on k(IAM) values using a mobile phase consisting of acetonitrile: Dulbecco's phosphate-buffered saline. The hepatic intrinsic clearance (CL'(int)) was calculated from in vitro disappearance half-life, and the oral bioavailability was predicted using in vitro hepatic clearance (CL(h)) and F(a). Significant correlations were observed for the relationships between predicted hepatic extraction ratios (ER(h)) and actual presystemic metabolism (r = 0.854) and between predicted and observed oral bioavailabilities (r = 0.805; p < 0.01). The IAM capacity factor together with the hepatic microsomal disappearance half-life may be useful in identifying compounds with high oral absorption potential in early drug discovery processes.

Physiologically based pharmacokinetics of zearalenone.

The objectives of this study were to (1) develop physiologically based pharmacokinetic (PBPK) models for zearalenone following intravenous (i.v.) and oral (p.o.) dosing in rats and (2) predict concentrations in humans via interspecies scaling. The model for i.v. dosing consisted of vein, artery, lung, liver, spleen, kidneys, heart, testes, brain, muscle, adipose tissue, stomach, and small intestine. To describe the secondary peak phenomenon observed after p.o. administration, the absorption model was constructed to reflect glucuronidation, biliary excretion, enterohepatic recirculation, and fast and slow absorption processes from the lumenal compartment. The developed models adequately described observed concentration-time data in rats after i.v. or p.o. administration. Upon model validation in rats, steady-state zearalenone concentrations in blood and tissues were simulated for rats after once daily p.o. exposures (0.1 mg/kg/d). The average steady-state blood zearalenone concentration predicted in rat was 0.014 ng/ml. Subsequently, a daily human p.o. dose needed to achieve the same steady-state blood concentration found in rats (0.014 ng/ml) was determined to be 0.0312 mg/kg/d or 2.18 mg/70 kg/d. The steady-state zearalenone concentration-time profiles in blood and tissues were also simulated for human after multiple p.o. administrations (dose 0.0312 mg/kg/d). The developed PBPK models adequately described the pharmacokinetics in rats and may be useful in predicting human blood and tissue concentrations for zearalenone under different p,o, exposure conditions.

Disposition, oral bioavailability, and tissue distribution of zearalenone in rats at various dose levels.

This study was conducted to characterize the disposition, oral bioavailability, and tissue distribution of zearalenone in rats. The pharmacokinetics and tissue distribution of zearalenone were studied after intravenous (i.v.) or oral (p.o.) administration at doses ranging from 1 to 8 mg/kg in intact and bile duct-cannulated rats. Serum, bile, and urine concentrations were determined by liquid chromatography and mass spectroscopy (LC/MS/MS) and tissue concentrations by high-performance liquid chromatography (HPLC)/fluorescence detection assays. Noncompartmental methods were used for pharmacokinetic analysis. Average Cl(s) (range 5.0-6.6 L/h/kg) and V(dss) (range 2-4.7 L/kg) remained unaltered over an i.v. dose range from 1 to 8 mg/kg, and area under the concentration-time curve (AUC) and initial peak concentrations increased linearly with dose. Minimal quantities of zearalenone were excreted unchanged in urine (f(e,urine) 0.5 +/- 0.2%) and bile (f(e,bile) 0.91 +/- 0.64%). After p.o. administration of 8 mg/kg, zearalenone was rapidly absorbed and serum concentration-time profiles showed a distinct second peak. The absolute oral bioavailability was low (2.7%). Comparing bile duct-cannulated to intact rats at a dose of 8 mg/kg, the impact of biliary excretion on overall pharmacokinetics was more pronounced after p.o. than after i.v. administration. Upon i.v. infusion to steady state, the highest zearalenone concentration was found in small intestine, followed by kidneys, liver, adipose tissue, and lung. Zearalenone concentrations in stomach, heart, brain, spleen, muscle, and testes were lower than those found in serum. The pharmacokinetics and tissue distribution data from this study may be useful to develop physiologically based pharmacokinetic (PBPK) models for zearalenone and subsequently to predict the pharmacokinetics and toxicity in humans.

Enhanced absorption and tissue distribution of paclitaxel following oral administration of DHP 107, a novel mucoadhesive lipid dosage form.

PURPOSE: This study was conducted to examine the absorption and tissue distribution characteristics of paclitaxel-loaded DHP 107, a Cremophor EL-free, mucoadhesive lipid oral dosage form. METHODS: DHP 107 was orally administered to mice at 10, 20 and 40 mg/kg doses. For comparison purposes, Taxol was i.v. injected at 5, 10 and 20 mg/kg doses. Drug levels were determined in plasma and tissues by validated HPLC assays. The absolute bioavailability and the relative distribution to various tissues were calculated as a function of dose. RESULTS: The dose-normalized plasma AUC(DHP 107)/AUC(Taxol) ratios calculated at comparable AUC values ranged from 14.6 to 29.0%. In contrast, relative tissue distribution ratios calculated as the dose-normalized AUC(DHP 107)/AUC(Taxol) were as high as 342.0, 139.0, 112.9 and 108.2% for stomach, small intestine, large intestine and ovary, respectively. CONCLUSIONS: Oral administration of DHP 107 provided a substantial systemic absorption of paclitaxel. Furthermore, the relative distribution ratios of DHP 107 at doses of 20 and 40 mg/kg were higher for stomach, small intestine, large intestine, and ovary than the systemic bioavailability, providing a basis for therapeutic advantages.