کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8513353 | 1556493 | 2018 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Inhibition of CYP3A by Antimalarial Piperaquine and Its Metabolites in Human Liver Microsomes With IVIV Extrapolation
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موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
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چکیده انگلیسی
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 1â²-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 minâ1 (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).
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 107, Issue 5, May 2018, Pages 1461-1467
Journal: Journal of Pharmaceutical Sciences - Volume 107, Issue 5, May 2018, Pages 1461-1467
نویسندگان
Mohd Yusmaidie Aziz, Kurt-Jürgen Hoffmann, Michael Ashton,