A methodology for finding optimal dosage levels in multi-drug treatment interactions

Barbosa, Marcos

doi:10.1016/0169-2607(94)90075-2

Cited by 2 publications

(1 citation statement)

References 9 publications

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“…To improve assay sensitivity, the summation of the signals from five transitions was used for standard curve and sample analysis . The standard curves with the concentrations ranged from 0.05 to 20 μg/mL were fitted to a quadratic regression model using weighting factors 1/ x . , Concentrations of 40k PEG and ATI-1072 were calculated using the Analyst software (Version 1.6, AB Sciex) based on their MRM responses and standard curves. Briefly, after the data acquisition of standards and unknown samples, a quantitative method was created in the quantitate mode for both PEG and ATI-1072.…”

Section: Experimental Detailsmentioning

confidence: 99%

Quantitative Analysis of Polyethylene Glycol (PEG) and PEGylated Proteins in Animal Tissues by LC-MS/MS Coupled with In-Source CID

Gong

Achanzar

et al. 2014

Anal. Chem.

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The covalent conjugation of polyethylene glycol (PEG, typical MW > 10k) to therapeutic peptides and proteins is a well-established approach to improve their pharmacokinetic properties and diminish the potential for immunogenicity. Even though PEG is generally considered biologically inert and safe in animals and humans, the slow clearance of large PEGs raises concerns about potential adverse effects resulting from PEG accumulation in tissues following chronic administration, particularly in the central nervous system. The key information relevant to the issue is the disposition and fate of the PEG moiety after repeated dosing with PEGylated proteins. Here, we report a novel quantitative method utilizing LC-MS/MS coupled with in-source CID that is highly selective and sensitive to PEG-related materials. Both (40K)PEG and a tool PEGylated protein (ATI-1072) underwent dissociation in the ionization source of mass spectrometer to generate a series of PEG-specific ions, which were subjected to further dissociation through conventional CID. To demonstrate the potential application of the method to assess PEG biodistribution following PEGylated protein administration, a single dose study of ATI-1072 was conducted in rats. Plasma and various tissues were collected, and the concentrations of both (40K)PEG and ATI-1072 were determined using the LC-MS/MS method. The presence of (40k)PEG in plasma and tissue homogenates suggests the degradation of PEGylated proteins after dose administration to rats, given that free PEG was absent in the dosing solution. The method enables further studies for a thorough characterization of disposition and fate of PEGylated proteins.

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Section: Experimental Detailsmentioning

confidence: 99%