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.
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.
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.
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.
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