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Inhibition of CYP3A by Antimalarial Piperaquine and Its Metabolites in Human Liver Microsomes With IVIV Extrapolation

Journal article
Authors Mohd Yusmaidie Aziz
Kurt-Jürgen Hoffmann
Michael Ashton
Published in Journal of Pharmaceutical Sciences
Volume 107
Issue 5
Pages 1461-1467
ISSN 0022-3549
Publication year 2018
Published at Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 1461-1467
Language en
Keywords piperaquine, CYP inhibition, drug-drug interaction, drug-drug interactions, plasmodium-falciparum malaria, mechanism-based, inhibition, time-dependent inhibition, in-vitro, dihydroartemisinin-piperaquine, clinical-trial, pharmacokinetics, midazolam, cytochromes-p450, Pharmacology & Pharmacy, Chemistry
Subject categories Pharmacology, Chemical Sciences


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 mu M(29), K-i = 0.68 mu M (29). In addition, piperaquine acted as a time-dependent inhibitor with IC50 declining to 0.32 mu M (28) during 30-min pre-incubation. Time-dependent inhibitor estimates were k(inact) = 0.024 min(-1) (30) and K-I = 1.63 mu M(17). Metabolite M2 was a highly potent reversible inhibitor with estimated IC50 and K-i values of 0.057 mu M (17) and 0.043 mu M (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). (C) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

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