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

Aziz, Mohd Yusmaidie,1984Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology (author)

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.

NATURVETENSKAP Kemi hsv//swe
NATURAL SCIENCES Chemical Sciences hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmakologi och toxikologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmacology and Toxicology hsv//eng
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

Hoffmann, Kurt-JürgenGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology (author)
Ashton, Michael,1955Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology(Swepub:gu)xashmi (author)
Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för farmakologi (creator_code:org_t)

By the author/editor: Aziz, Mohd Yusma ...; Hoffmann, Kurt-J ...; Ashton, Michael, ...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmacology and ...

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