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      Method Development and Validation for Measuring O 6-Methylguanine in Dried Blood Spot Using Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry

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          Abstract

          Background

          Cyclophosphamide is a nitrogen mustard chemotherapy drug that damages DNA through alkylation in the DNA base and produces DNA adducts. Alkylation that occurs in the N7 position of guanine base has a cytotoxic effect which is useful for cancer therapy. However, the alkylation that occurs in the O6 position of guanine bases can have mutagenic and carcinogenic effects that can trigger secondary cancer. This carcinogenic compound can be found in very low concentrations in cancer patients who had been receiving alkylating agents as their anticancer therapy. Analysis of O 6-methylguanine can be one of the ways of therapeutic drug monitoring to avoid secondary cancer risk. This study aims to develop a sensitive, selective, and validated analytical method using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS).

          Methods

          Analysis of O 6-methylguanine was done in Dried Blood Spot (DBS) and using allopurinol as an internal standard. The optimal analysis conditions were obtained using a C18 Acquity ® Bridged Ethylene Hybrid (BEH) column (1.7 µm, 100 mm x 2.1 mm); mobile phase was 0.05% formic acid - acetonitrile (95:5 v/v); flow rate 0.1 mL/minute; gradient elution for 6 minutes; and detection at m/z 165.95 > 149 for O 6-methylguanine and m/z 136.9 > 110 for allopurinol.

          Results

          The present study has fulfilled the FDA validation parameter requirements. The method provides rapid, sensitive, and selective analysis of O 6-methylguanine using UPLC-MS/MS with a linear concentration range between 0.5–20 ng/mL.

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          Most cited references 15

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          Therapeutic Drug Monitoring by Dried Blood Spot: Progress to Date and Future Directions

          This article discusses dried blood spot (DBS) sampling in therapeutic drug monitoring (TDM). The most important advantages of DBS sampling in TDM are the minimally invasive procedure of a finger prick (home sampling), the small volume (children), and the stability of the analyte. Many assays in DBS have been reported in the literature over the previous 5 years. These assays and their analytical techniques are reviewed here. Factors that may influence the accuracy and reproducibility of DBS methods are also discussed. Important issues are the correlation with plasma/serum concentrations and the influence of hematocrit on spot size and recovery. The different substrate materials are considered. DBS sampling can be a valid alternative to conventional venous sampling. However, patient correlation studies are indispensable to prove this. Promising developments are dried plasma spots using membrane and hematocrit correction using the potassium concentration.
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            Dried Blood Spot Collection of Health Biomarkers to Maximize Participation in Population Studies

            Biomarkers are directly-measured biological indicators of disease, health, exposures, or other biological information. In population and social sciences, biomarkers need to be easy to obtain, transport, and analyze. Dried Blood Spots meet this need, and can be collected in the field with high response rates. These elements are particularly important in longitudinal study designs including interventions where attrition is critical to avoid, and high response rates improve the interpretation of results. Dried Blood Spot sample collection is simple, quick, relatively painless, less invasive then venipuncture, and requires minimal field storage requirements (i.e. samples do not need to be immediately frozen and can be stored for a long period of time in a stable freezer environment before assay). The samples can be analyzed for a variety of different analytes, including cholesterol, C-reactive protein, glycosylated hemoglobin, numerous cytokines, and other analytes, as well as provide genetic material. DBS collection is depicted as employed in several recent studies.
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              Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19.

              Cyclophosphamide (CP), a widely used cytostatic, is metabolized by polymorphic drug metabolizing enzymes particularly cytochrome P450 (CYP) enzymes. Its side effects and clinical efficacy exhibit a broad interindividual variability, which might be due to differences in pharmacokinetics. CP-kinetics were determined in 60 patients using a global and a population pharmacokinetic model considering functionally relevant polymorphisms of CYP2B6, CYP2C9, CYP2C19, CYP3A5, and GSTA1. Moreover, metabolic ratios were calculated for selected CP metabolites, analyzed by (31)P-NMR-spectroscopy. Analysis of variance revealed that the CYP2C19*2 genotype influenced significantly pharmacokinetics of CP at doses
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                03 March 2021
                2021
                : 15
                : 963-971
                Affiliations
                [1 ]Faculty of Pharmacy, Universitas Indonesia , Depok, West Java, 16424, Indonesia
                [2 ]Indonesia Defense University , Bogor, 16810, West Java, Indonesia
                Author notes
                Correspondence: Yahdiana Harahap Email yahdiana@farmasi.ui.ac.id
                Article
                283775
                10.2147/DDDT.S283775
                7937437
                © 2021 Harahap et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 3, Tables: 6, References: 15, Pages: 9
                Categories
                Original Research

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