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Bioanalytical method development and validation of MES207, a neuropeptide FF receptor antagonist, and its application in preclinical pharmacokinetics.

ABSTRACT: The nonpeptide small molecule, MES207, exhibits 17-fold preferential binding to the neuropeptide FF receptor 1 (NPFFR1) over NPFFR2 and shows antagonist functionality at NPFF receptors. In order to further the development of MES207 as a NPFFR1 probe, an UPLC-MS/MS bioanalytical method was developed and validated to quantify MES207 in rat plasma for a linearity range of 3-200?ng/mL. The method was applied in the analysis of the plasma, brain, and urine samples collected during pharmacokinetic studies in healthy male and female Sprague Dawley rats. The animals were dosed through oral gavage (50?mg/kg) and intravenously (2.5?mg/kg). Test samples were analyzed using the validated bioanalytical method to generate plasma concentration-time profiles. The results were further subjected to non-compartmental analysis using Phoenix 6.4®. MES207 exhibits a large volume of distribution (1.2?±?0.6?L), high clearance (0.8?±?0.1?L/h), and a poor oral bioavailability (1.7?±?0.4%). The compound also showed a multiple peak phenomenon with a very short absorption phase. It appears that gender does not significantly influence the differences in pharmacokinetic parameters of this NPFF probe.

SUBMITTER: King TI

PROVIDER: S-EPMC7027589 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Bioanalytical method development and validation of MES207, a neuropeptide FF receptor antagonist, and its application in preclinical pharmacokinetics.

King Tamara I TI Roewekamp Ann-Cathrin AC Sharma Abhisheak A Harrison Sydney S Mesangeau Christophe C Mottinelli Marco M Kamble Shyam H SH McCurdy Christopher R CR Avery Bonnie A BA

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 20191112

The nonpeptide small molecule, MES207, exhibits 17-fold preferential binding to the neuropeptide FF receptor 1 (NPFFR1) over NPFFR2 and shows antagonist functionality at NPFF receptors. In order to further the development of MES207 as a NPFFR1 probe, an UPLC-MS/MS bioanalytical method was developed and validated to quantify MES207 in rat plasma for a linearity range of 3-200 ng/mL. The method was applied in the analysis of the plasma, brain, and urine samples collected during pharmacokinetic stu ...[more]

PMID: 31790916

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Project description:IntroductionIn the development of cell therapy products for human use, studies on the biodistribution of transplanted cells in animals are important for assessing the safety and efficacy of these products. Although a few reports have described the biodistribution of human cells in animals using Arthrobacter luteus-based-polymerase chain reaction (Alu-PCR), most have used genomic DNA or synthetic oligonucleotide as calibrators, as opposed to actual cells. In addition, bioanalytical variability in the quantification of cells with respect to specificity, selectivity, accuracy, and precision, has not been evaluated. Accordingly, in this study, we validated the utility of this bioanalytical method for human T cells in mice to establish assay performance using cells as a calibrator.MethodsA standard curve was constructed for the addition of cell lysates to mouse tissues and blood, and DNA was extracted. Alu-PCR was applied for the quantification of human peripheral blood CD8+ T cells in mice. To determine assay performance, we evaluated accuracy, precision, selectivity, specificity, and stability. In vivo cell kinetics and biodistribution were investigated based on intravenous administration of human T cells to mice.ResultsAlu-PCR enabled us to specifically detect human T cells in mouse blood and tissues. The lower detection limit of Alu-PCR was 10 cells/15 mg tissue (7.5 mg for spleen and lung) or cells/50 μL blood. Given that PCR threshold cycle (Cq) values among mouse samples (blood, liver spleen, lung, heart, and kidney) show slight variation, calibration curves should be generated using the same tissue as used for the assay. Most coefficients of variation in the assay were within 30%. The cell kinetics of administered human T cells in mice were successfully evaluated using the established Alu-qPCR.ConclusionsThe Alu-PCR technique developed in this study showed sufficient specificity and sensitivity in detecting human peripheral blood CD8+ T cells in mice. This technique, which targets the primate-specific Alu gene, is applicable for quantifying transplanted human cells in animals without the necessity of cell labeling. The data presented herein will be useful for standardizing bioanalytical approaches in biodistribution studies of cell therapy products.

Dataset Information

Bioanalytical method development and validation of MES207, a neuropeptide FF receptor antagonist, and its application in preclinical pharmacokinetics.

Publications

Bioanalytical method development and validation of MES207, a neuropeptide FF receptor antagonist, and its application in preclinical pharmacokinetics.

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