Utilization of Liver Microsomes to Estimate Hepatic Intrinsic Clearance of Monoamine Oxidase Substrate Drugs in Humans.
Utilization of Liver Microsomes to Estimate Hepatic Intrinsic Clearance of Monoamine Oxidase Substrate Drugs in Humans.
复制标题
利用肝微粒体估计人类单胺氧化酶底物药物的肝脏内在清除率。
DOI：
10.1007/s11095-017-2140-4
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Kato Y.
中科院分区：
文献类型：
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作者：
Masuo Y;Nagamori S;Hasegawa A;Hayashi K;Isozumi N;Nakamichi N;Kanai Y;Kato Y.
目的单胺氧化酶(MAO)是一种非CYP酶，定位于线粒体膜上，具有清除治疗药物的作用。本研究的目的是验证利用人肝微粒体(HLMS)定量估计MAO底物药物的代谢清除率。方法选择3种MAO底物药物舒马曲普坦、利扎曲坦和苯肾上腺素，以及4种CYP底物，测量它们在与HLMS或线粒体孵育过程中的消失率。结果在10个人的肝脏中，舒马曲普坦和一种典型的MAO底物5-羟色胺在HLMS中的CL与HLMT中的CL相关。从CL估算的肝固有清除量(CLINT，体外)分别比文献中获得的MAO和CYP底物的活体肝固有清除量(CLINT，vivo)低14-20倍和2-5倍。用蛋白质组学方法进一步验证了利用HLMS定量评估MAO底物的代谢清除能力，发现HLMS和HLMT中均检测到大量位于线粒体内外膜上的蛋白质。结论HLMS可定量评估MAO底物药物的体外效价，可用于半定量预测CLINT、VIVOVALS。
PurposeMonoamine oxidases (MAOs) are non-CYP enzymes that contribute to systemic elimination of therapeutic agents, and localized on mitochondrial membranes. The aim of the present study was to validate quantitative estimation of metabolic clearance of MAO substrate drugs using human liver microsomes (HLMs).MethodsThree MAO substrate drugs, sumatriptan, rizatriptan and phenylephrine, as well as four CYP substrates were selected, and their disappearance during incubation with HLMs or mitochondria (HLMt) was measured. Metabolic clearance (CL) was then calculated from the disappearance curve.ResultsCL obtained in HLMs for sumatriptan and a typical MAO substrate serotonin was correlated with that obtained in HLMt among ten human individual livers. Hepatic intrinsic clearance (CLint,vitro) estimated from CL in HLMs was 14–20 and 2–5 times lower thanin vivohepatic intrinsic clearance (CLint,vivo) obtained from literature for MAO and CYP substrates, respectively. Utilization of HLMs for quantitatively assessing metabolic clearance of MAO substrates was further validated by proteomics approach which has revealed that numerous proteins localized on inner and outer membranes of mitochondria were detected in both HLMs and HLMt.ConclusionCLint,vitrovalues of MAO substrate drugs can be quantitatively estimated with HLMs and could be used for semi-quantitative prediction of CLint,vivovalues.