Departmental Bulletin Paper 2 コンパートメント−肝薬物貯槽−融合型 tube モデルを用いたフルボキサミン併用による薬物間相互作用のシミュレーションと in-vivo 酵素阻害定数の見積もり
Simulation of metabolic drug-drug interactions perpetrated by fluvoxamine through the use of hybridized two-compartment hepatic drug-pool-based tube modeling and estimation of in-vivo inhibition constants
伊賀, 勝美
IGA, Katsumi

 Co-administration of fluvoxamine (perpetrator) and ramelteon (victim, high-clearance CYP1A2 substrate) has been reported to show a 130-fold increase in the area under the bloodramelteon-levels curve (AUCR), which is unpredictable by any method assuming the traditional ws-Eh model. Thus, in order to predict this drug-drug interaction (DDI), a mathematical method that allows for the simulation of dynamic changes in blood victim levels in response to metabolic inhibition by a perpetrator, without the use of any specialized tool, was derived from hybridized two-compartment hepatic drug-pool-based tube modeling. Using this method, the ramelteon-victimized DDI was able to be simulated in comparison with other victim DDIs, assuming a consistent fluvoxamine dosing regimen. Despite great difference in the AUCRs, CYP1A2 or CYP2C19 substrate-victimized DDIs resulted in equivalent inhibition constants (Ki, around 3 nM) and net enzymatic inhibitory activities calculated by eliminating hepatic availability increases for the victims. Thus, the unusually large ramelteon DDI could be attributed to the Eh of ramelteon itself. This DDI risk could also be accurately predicted from Ki values estimated in the other CYP1A2 or CYP2C19-substrate interactions. Meanwhile, dynamic changes in the blood perpetrator levels were demonstrated to have a small effect on DDI, suggesting the usefulness of a tube-based static method for DDI prediction.

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