Inhibition of CYP3A by antimalarial piperaquine and its metabolites in human liver microsomes with IVIV extrapolation

The potential of the antimalarial piperaquine and its metabolites to inhibit CYP3A was investigated in pooled human liver microsomes. CYP3A activity was measured by LC-MS/MS 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 (TDI) with IC50 declining to 0.32 μM (28) during 30 min pre-incubation.

The potential of the antimalarial piperaquine and its metabolites to inhibit CYP3A was investigated in pooled human liver microsomes. CYP3A activity was measured by LC-MS/MS 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 (TDI) with IC50 declining to 0.32 μM (28) during 30 min pre-incubation.