Inhibitory effects of amiodarone on simvastatin metabolism in human liver microsomes
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Abstract
Objective To investigate the effects of amiodarone (AMD) on simvastatin (SV) in human liver microsomes and the possible underlying mechanisms. Methods Time-, NADPH- and concentration-dependent inhibitions were tested in HLM. The logarithm of relative inhibition values was plotted versus preincubation time (0, 5, 10, 15, 20min) for a series concentration of AMD used (0, 2, 5, 25, 50μmol/L), and the slopes determined by linear regression. These slope values represente the observed inactivation rate constants (kobs). A double-reciprocal plot was then constructed using the reciprocal of the kobs (y-axis) and the reciprocal of the associated inhibitor concentration (x-axis) to estimate the values of kinact and KI, which were two principal kinetic constants that were specific for mechanism-based inhibition (MBI).drug-drug interactions (DDI) potential was predicted based on in vitro data and by using the in vitro-in vivo extrapolation. Results The time-, concentration- and NADPH-dependent characteristics confirmed that when SV was the substrate of CYP3A4, the inhibition of AMD to CYP3A4 is MBI. KI and kinact value were calculated to be 5.1μmol/L and 0.018min-1. The CLint of SV was reduced 2.96-5.63 fold when it was administrated with AMD. Conclusion Based on the results, AMD would inhibit SV metabolism via the mechanism-based manner, which would lead to DDI when they are taken together. Careful clinical observation is recommended when AMD and SV have to be simultaneously prescribed.
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