Pharmacokinetic Parameters and Tissue Withdrawal Intervals for Sheep Administered Multiple Oral Doses of Meloxicam

Meloxicam is an anti-inflammatory drug used to treat pain and inflammation in ruminants including sheep, and pharmacokinetic studies are needed to protect the food supply from drug residues after use in food-producing animals. This study estimated plasma pharmacokinetic parameters and meat withdrawal intervals (WDI) for market sheep after multiple daily oral doses of meloxicam. Single and multiple dose plasma pharmacokinetic studies, a multi-dose tissue depletion study, and a follow-up study to investigate if events prior to slaughter were associated with differences in plasma meloxicam concentrations, all using sample data collected after completion of dosing, were completed. Using regulatory agency methods for calculating withdrawal times, an estimated WDI of at least 10 d following the last dose is recommended for market lambs treated with 10 daily oral 1 mg/kg doses of meloxicam tablets suspended in water. The effect of events surrounding slaughter on plasma meloxicam concentrations in lambs is unknown but should be considered if plasma samples are obtained immediately prior to or during the slaughter process and used for pharmacokinetic investigations.

Development and Optimization of a High Sensitivity LC-MS/MS Method for the Determination of Hesperidin and Naringenin in Rat Plasma: Pharmacokinetic Approach

The purpose of this study was to develop, optimize, and fully validate a high-sensitivity methodology using UHPLC-MS/MS to simultaneously quantify hesperidin and naringenin in microsamples (100 µL) of murine plasma after intragastric administration of single pure flavonoids and a mixture. The optimization process allowed for high sensitivity with detection limits of approximately picogram order using an electrospray ionization (ESI) source in negative mode and an experiment based on multiple reaction monitoring (MRM). The validation parameters showed excellent linearity and detection limits, with a precision of less than 8% and a recovery of over 90%. This methodology was applied to compare the pharmacokinetic parameters for the administration of hesperidin and naringenin in individual form or in the form of a mixture. The results showed an absence of significant effects (p > 0.05) for Tmax and Cmax; however, the AUC presented significant differences (p < 0.05) for both flavonoids when administered as a mixture, showing an improved absorption ratio for both flavonoids.

Sensitive Inexpensive HPLC Determination of Novel Anticancer Combination in Nanoparticles and Rat Plasma: Pharmacokinetic Application

Two high-performance liquid chromatography-diode array detection methods have been developed and validated for the simultaneous quantification of genistein (GNS) and all trans retinoic acid (ATRA) as a novel anticancer combination therapy in their co-formulated nanoparticles and in rat plasma. Separation was performed on C18 column (250 × 4.6 mm, 5 μm) using celecoxib as internal standard. A mobile phase containing acetonitrile and water adjusted to pH 3 using 1% trifluoroacetic acid was delivered in gradient elution modes with time programmed UV detection. For extraction of the drugs and the internal standard from rat plasma, liquid- liquid extraction was applied. The proposed methods were validated as per International Conference on Harmonisation (ICH) guidelines (in the range 0.1–10 μg/mL for analysis of GNS and ATRA in nanoparticles) or according to Food and Drug Administration (FDA) guidance on bioanalytical method validation (in the range 0.025–20 μg/mL for analysis of GNS and ATRA in rat plasma). Pharmacokinetic study in six rats was performed following intravenous (IV) administration of a single dose of 0.5 mg/Kg of GNS and ATRA. The drugs’ concentrations were measured up to 24 hours, and different pharmacokinetic parameters were calculated. The obtained parameters were comparable with the reported values for IV administration of each drug alone in rats. This confirms the applicability of the proposed method in monitoring the levels of the two drugs in vivo following their coadministration and indicating that the two drugs could be coadministered as a promising novel combination therapy for the treatment of lung cancer without great alteration in their pharmacokinetic parameters compared with their individual IV administration.

Double PEGylation Significantly Improves Pharmacokinetic Properties of Irinotecan Containing Nanoparticles in a Zebrafish Model

Background: Plasma pharmacokinetic (PK) properties of oral or injectable drugs dictate whether the drug is clinically viable or not. Poor PK properties often result in termination of the development of the drug. Optimizing PK properties of drugs is a major challenge in the pharmaceutical industry. Ideally, sufficient circulating time of the drug in the plasma is required, so that it has adequate opportunity to reach the target tissue. Methods: We have used irinotecan, a known drug with poor PK properties, as a prototype to apply our idea of improving PK in plasma by PEGylation. We compared the PK profile of free irinotecan, irinotecan packaged in nanoparticles (NPs) with single polyethylene glycol (PEG) layer and irinotecan packaged in NPs with double PEG layer. PK properties of these formulations were compared in a zebrafish model when given intraperitoneally. Results: Dramatic differences in the PK properties of the three formulations were observed. The AUC, Cmax and T1/2 of irinotecan in each of these formulations differed from each other significantly. Approx. 4.5 - fold higher peak concentration (Cmax) and ~3 - fold higher exposure (AUC0-t) were observed for double PEGylated NPs as compared to free irinotecan and single PEGylated NPs. Conclusion: In summary, our data suggest that double PEGylation of NPs could be a very effective way to improve PK properties of drugs such as irinotecan.