Objective To investigate the effects ofamiodarone （AMD） on simvastatin （SV） in human liver microsomes and the possible underlying mechanisms. Methods Time-, NADPH- and concentration-dependent inhibitions were test...Objective To investigate the effects ofamiodarone （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, 50 umol/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 K1, 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 5.1umol/L and 0.018minL The CLant 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.展开更多
文摘Objective To investigate the effects ofamiodarone （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, 50 umol/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 K1, 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 5.1umol/L and 0.018minL The CLant 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.
