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  1. LC-MS/MS quantitation of antimalarial drug piperaquine and metabolites in human plasma
    Aziz MY, Hoffmann KJ, Ashton M
    J Chromatogr B Analyt Technol Biomed Life Sci, 2017 Sep 15;1063:253-258.
    PMID: 28863865 DOI: 10.1016/j.jchromb.2017.06.035
    PURPOSE: This study aimed to develop a sensitive, quantitative assay for the antimalarial piperaquine (PQ) and its metabolites M1 and M2 in human plasma.

    RESULTS: Analytes were gradiently separated on a C18 column and detected with a Sciex API 4000 MS/MS with an ESI source operated in the positive ion mode with deuterated PQ as internal standard. The response was linear in the range 3.9-2508nM with a runtime of 7.0min per sample. The method was applied to clinical samples from healthy volunteers.

    CONCLUSION: This LC-MS/MS method for the simultaneous quantitation of PQ and two of its metabolites in plasma may prove helpful for assessment of metabolite safety issues in vivo.

    Matched MeSH terms: Quinolines/metabolism
  2. Synthesis of novel quinoline-based thiadiazole, evaluation of their antileishmanial potential and molecular docking studies
    Almandil NB, Taha M, Rahim F, Wadood A, Imran S, Alqahtani MA, et al.
    Bioorg Chem, 2019 04;85:109-116.
    PMID: 30605884 DOI: 10.1016/j.bioorg.2018.12.025
    New series of quinoline-based thiadiazole analogs (1-20) were synthesized, characterized by EI-MS, 1H NMR and 13C NMR. All synthesized compounds were subjected to their antileishmanial potential. Sixteen analogs 1-10, 12, 13, 16, 17, 18 and 19 with IC50 values in the range of 0.04 ± 0.01 to 5.60 ± 0.21 µM showed tremendously potent inhibition as compared to the standard pentamidine with IC50 value 7.02 ± 0.09 µM. Analogs 11, 14, 15 and 20 with IC50 8.20 ± 0.35, 9.20 ± 0.40, 7.20 ± 0.20 and 9.60 ± 0.40 µM respectively showed good inhibition when compared with the standard. Structure-activity relationships have been also established for all compounds. Molecular docking studies were performed to determine the binding interaction of the compounds with the active site target.
    Matched MeSH terms: Quinolines/metabolism
  3. Inhibition of CYP3A by Antimalarial Piperaquine and Its Metabolites in Human Liver Microsomes With IVIV Extrapolation
    Aziz MY, Hoffmann KJ, Ashton M
    J Pharm Sci, 2018 05;107(5):1461-1467.
    PMID: 29352982 DOI: 10.1016/j.xphs.2018.01.009
    The potential of the antimalarial piperaquine and its metabolites to inhibit CYP3A was investigated in pooled human liver microsomes. CYP3A activity was measured by liquid chromatography-tandem mass spectrometry as the rate of 1'-hydroxymidazolam formation. Piperaquine was found to be a reversible, potent inhibitor of CYP3A with the following parameter estimates (%CV): IC50 = 0.76 μM (29), Ki = 0.68 μM (29). In addition, piperaquine acted as a time-dependent inhibitor with IC50 declining to 0.32 μM (28) during 30-min pre-incubation. Time-dependent inhibitor estimates were kinact = 0.024 min-1 (30) and KI = 1.63 μM (17). Metabolite M2 was a highly potent reversible inhibitor with estimated IC50 and Ki values of 0.057 μM (17) and 0.043 μM (3), respectively. M1 and M5 metabolites did not show any inhibitory properties within the limits of assay used. Average (95th percentile) simulated in vivo areas under the curve of midazolam increased 2.2-fold (3.7-fold) on the third which is the last day of piperaquine dosing, whereas for its metabolite M2, areas under the curve of midazolam increased 7.7-fold (13-fold).
    Matched MeSH terms: Quinolines/metabolism
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