Palacharla Raghava Choudary, Molgara Parusharamulu, Panthangi Hanumanth Rao, Boggavarapu Rajesh Kumar, Manoharan Arun Kumar, Ponnamaneni Ranjith Kumar, Ajjala Devender Reddy, Nirogi Ramakrishna
a Drug Metabolism and Pharmacokinetics , Suven Life Sciences Ltd , Hyderabad , India.
b Bio-analysis , Suven Life Sciences Ltd , Medak , India.
Xenobiotica. 2019 Feb;49(2):169-176. doi: 10.1080/00498254.2018.1434913. Epub 2018 Feb 15.
The objective is to evaluate methoxsalen as an in vitro phenotyping tool in comparison to ABT as a nonspecific inactivator of P450 mediated metabolism. The reversible inhibition of methoxsalen and ABT against the P450, FMO, AO, MAO-A and -B, enzymes were evaluated using standard marker probe reactions. The time-dependent inhibition of P450 enzymes was evaluated in human liver microsomes. CES1 activities were determined by monitoring the depletion of known substrate, the clopidogrel. The metabolism of P450 substrates in the presence and absence of methoxsalen or ABT was evaluated in human liver microsomes. Methoxsalen is a direct inhibitor and inhibited the activities (>90%) of all enzymes at a concentration of 300 µM except for CYP2C9. Methoxsalen is also a potent time-dependent inhibitor of all P450 enzymes except for CYP2C19 (moderate) at a concentration of 300 µM. Methoxsalen inhibited the metabolism of P450 substrates in the pre-incubation mode. ABT is a potent TDI of several P450 except for CYP2C19 (47%) and CYP2C9 (27%). The results indicate that methoxsalen is a potent pan P450 inhibitor than ABT and can be a better tool in distinguishing P450 mediated metabolism form non-P450 metabolism in human liver microsomes.
目的是评估甲氧沙林作为一种体外表型分析工具，并与作为P450介导代谢的非特异性灭活剂的ABT进行比较。使用标准标记探针反应评估甲氧沙林和ABT对P450、FMO、AO、MAO - A和 - B酶的可逆抑制作用。在人肝微粒体中评估P450酶的时间依赖性抑制作用。通过监测已知底物氯吡格雷的消耗来测定CES1活性。在人肝微粒体中评估在存在和不存在甲氧沙林或ABT的情况下P450底物的代谢。甲氧沙林是一种直接抑制剂，在300 μM浓度下除CYP2C9外抑制所有酶的活性（>90%）。在300 μM浓度下，甲氧沙林也是除CYP2C19（中等）外所有P450酶的强效时间依赖性抑制剂。甲氧沙林在预孵育模式下抑制P450底物的代谢。ABT是几种P450的强效TDI，除CYP2C19（47%）和CYP2C9（27%）外。结果表明，甲氧沙林是一种比ABT更强效的泛P450抑制剂，并且在区分人肝微粒体中P450介导的代谢与非P450代谢方面可能是一种更好的工具。
