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Determination of ZSTK474, a novel Pan PI3K inhibitor in mouse plasma by LC-MS/MS and its application to Pharmacokinetics.

Abstract

ZSTK474, a promising novel anticancer molecule derived from s-triazine, found to have antitumor activities against different cancer cell lines. However, neither LCMS method nor pharmacokinetics of ZSTK474 has been reported till now. A sensitive, simple, short and specific liquid chromatography tandem mass spectrometry (LCMS/MS) method was developed for the quantification of ZSTK474 in mouse plasma accordance with the US Food and Drug Administration guidelines. Extraction of drug molecule was carried out using protein precipitation. Chromatographic analyte separation was achieved on Atlantis dC18 (4.6×50mm, 3μm). Composition of isocratic mobile phase consists of 90% acetonitrile and 0.2% formic acid, at 0.7mL/min flow rate, having short 2.5min run time. Method development was validated and found to be linear over a dynamic range between 1.9-1000ng/mL; having a correlation coefficient (r 2)≥0.9978. The analyte was found to be stable under short and long term storage conditions. LCMS/MS method developed was validated and found to be selective, reproducible, precise and accurate to quantify ZSTK474 in plasma samples, and first time successfully applied to pharmacokinetic studies. Pharmacokinetic data showed fast absorption attaining Cmax at 0.25h and half life (t1/2) 5.18h after oral administration of ZSTK474 at 20mg/kg in mouse.

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  • Authors+Show Affiliations

    ,

    Academy Council of Scientific and Industrial Research (AcSIR), New Delhi, 110001, India; PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India. Electronic address: amarinder_pharma@yahoo.co.in.

    ,

    Academy Council of Scientific and Industrial Research (AcSIR), New Delhi, 110001, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.

    ,

    PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.

    ,

    PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.

    ,

    Dept. of Pharmacy, JJT University, Jhunjhunu, Rajasthan, 333001, India.

    ,

    PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.

    ,

    Academy Council of Scientific and Industrial Research (AcSIR), New Delhi, 110001, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.

    ,

    Academy Council of Scientific and Industrial Research (AcSIR), New Delhi, 110001, India; PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.

    ,

    Quality Control & Quality Assurance Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.

    ,

    PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.

    ,

    Academy Council of Scientific and Industrial Research (AcSIR), New Delhi, 110001, India; PK-PD-Toxicology and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India. Electronic address: singh_gd@iiim.ac.in.

    Academy Council of Scientific and Industrial Research (AcSIR), New Delhi, 110001, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.

    Source

    MeSH

    Animals
    Chromatography, High Pressure Liquid
    Female
    Guidelines as Topic
    Mice
    Mice, Inbred BALB C
    Phosphatidylinositol 3-Kinases
    Protein Kinase Inhibitors
    Reproducibility of Results
    Spectrometry, Mass, Electrospray Ionization
    Tandem Mass Spectrometry
    Triazines
    United States
    United States Food and Drug Administration

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    29175554

    Citation

    Singh, Amarinder, et al. "Determination of ZSTK474, a Novel Pan PI3K Inhibitor in Mouse Plasma By LC-MS/MS and Its Application to Pharmacokinetics." Journal of Pharmaceutical and Biomedical Analysis, vol. 149, 2018, pp. 387-393.
    Singh A, Thatikonda T, Kumar A, et al. Determination of ZSTK474, a novel Pan PI3K inhibitor in mouse plasma by LC-MS/MS and its application to Pharmacokinetics. J Pharm Biomed Anal. 2018;149:387-393.
    Singh, A., Thatikonda, T., Kumar, A., Wazir, P., V, V., Nandi, U., ... Vishwakarma, R. (2018). Determination of ZSTK474, a novel Pan PI3K inhibitor in mouse plasma by LC-MS/MS and its application to Pharmacokinetics. Journal of Pharmaceutical and Biomedical Analysis, 149, pp. 387-393. doi:10.1016/j.jpba.2017.11.031.
    Singh A, et al. Determination of ZSTK474, a Novel Pan PI3K Inhibitor in Mouse Plasma By LC-MS/MS and Its Application to Pharmacokinetics. J Pharm Biomed Anal. 2018 Feb 5;149:387-393. PubMed PMID: 29175554.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Determination of ZSTK474, a novel Pan PI3K inhibitor in mouse plasma by LC-MS/MS and its application to Pharmacokinetics. AU - Singh,Amarinder, AU - Thatikonda,Thanusha, AU - Kumar,Amit, AU - Wazir,Priya, AU - V,Vijayabhaskar, AU - Nandi,Utpal, AU - Singh,Parvinder Pal, AU - Singh,Surjeet, AU - Gupta,Ajay Prakash, AU - Tikoo,Manoj K, AU - Singh,Gurdarshan, AU - Vishwakarma,Ram, Y1 - 2017/11/11/ PY - 2017/08/27/received PY - 2017/11/07/revised PY - 2017/11/08/accepted PY - 2017/11/28/pubmed PY - 2018/8/14/medline PY - 2017/11/28/entrez KW - LCMS/MS KW - Mouse plasma KW - PI3K inhibitor KW - Pharmacokinetics KW - Protein precipitation KW - ZSTK474 SP - 387 EP - 393 JF - Journal of pharmaceutical and biomedical analysis JO - J Pharm Biomed Anal VL - 149 N2 - ZSTK474, a promising novel anticancer molecule derived from s-triazine, found to have antitumor activities against different cancer cell lines. However, neither LCMS method nor pharmacokinetics of ZSTK474 has been reported till now. A sensitive, simple, short and specific liquid chromatography tandem mass spectrometry (LCMS/MS) method was developed for the quantification of ZSTK474 in mouse plasma accordance with the US Food and Drug Administration guidelines. Extraction of drug molecule was carried out using protein precipitation. Chromatographic analyte separation was achieved on Atlantis dC18 (4.6×50mm, 3μm). Composition of isocratic mobile phase consists of 90% acetonitrile and 0.2% formic acid, at 0.7mL/min flow rate, having short 2.5min run time. Method development was validated and found to be linear over a dynamic range between 1.9-1000ng/mL; having a correlation coefficient (r 2)≥0.9978. The analyte was found to be stable under short and long term storage conditions. LCMS/MS method developed was validated and found to be selective, reproducible, precise and accurate to quantify ZSTK474 in plasma samples, and first time successfully applied to pharmacokinetic studies. Pharmacokinetic data showed fast absorption attaining Cmax at 0.25h and half life (t1/2) 5.18h after oral administration of ZSTK474 at 20mg/kg in mouse. SN - 1873-264X UR - https://www.unboundmedicine.com/medline/citation/29175554/Determination_of_ZSTK474,_a_novel_Pan_PI3K_inhibitor_in_mouse_plasma_by_LC-MS/MS_and_its_application_to_Pharmacokinetics L2 - https://linkinghub.elsevier.com/retrieve/pii/S0731-7085(17)32164-7 DB - PRIME DP - Unbound Medicine ER -