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首页> 外文期刊>Regulatory Toxicology and Pharmacology: RTP >Plasma concentrations of melengestrol acetate in humans extrapolated from the pharmacokinetics established in in vivo experiments with rats and chimeric mice with humanized liver and physiologically based pharmacokinetic modeling
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Plasma concentrations of melengestrol acetate in humans extrapolated from the pharmacokinetics established in in vivo experiments with rats and chimeric mice with humanized liver and physiologically based pharmacokinetic modeling

机译：从人体内肝脏和生理基础的药代动力学模型对大鼠和嵌合小鼠体内实验中建立的药代动力学推算出人体中乙酸美仑孕酮的血浆浓度

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摘要

Some synthetic chemicals are suspected to be responsible for adverse effects on endocrine function. Sex hormones administered to farm animals are of particular interest because of their regulatory role in developmental processes. To predict concentrations in humans of the synthetic growth promoter melengestrol acetate (17α-acetoxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione), a forward dosimetry approach was carried out using data from no-observed-adverse-effect-level doses orally administered to mice or rats and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated 2-hydroxylation of melengestrol acetate, but rodent livers produced additional unidentified hydroxymetabolites. Adjusted animal biomonitoring equivalents for melengestrol acetate from mouse and rat studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. Melengestrol acetate elimination in humans was estimated to be slow compared with elimination in rodents. The disposition of melengestrol acetate in humans was evaluated using chimeric TK-NOG mice with humanized liver. The results suggest the usefulness of simplified PBPK modeling combined with in vitro and in vivo experiments and literature resources as well as a future interest in estimating by a full PBPK modeling using another bottom up system. This model may also be useful for risk evaluation and for simulating plasma concentrations resulting from exposure to low doses of melengestrol acetate and related compounds.
机译：怀疑某些合成化学物质会对内分泌功能产生不良影响。施用给农场动物的性激素特别受关注，因为它们在发育过程中起着调节作用。为了预测合成生长促进剂醋酸美仑孕酮（17α-乙酰氧基-6-甲基-16-亚甲基孕烷-4,6-二烯-3,20-二酮）在人体中的浓度，使用了来自观察到的对小鼠或大鼠以及人体和啮齿类动物体外实验的不良剂量。人肝微粒体优先介导乙酸美仑孕酮的2-羟基化，但啮齿动物肝脏产生了另外的未鉴定的羟基代谢物。使用已知的物种异速缩放比例因子和人类代谢数据以及简单的基于生理学的药代动力学（PBPK）模型，将来自小鼠和大鼠研究的醋酸美仑孕酮的调整后的动物生物监控当量换算为人类生物监控当量。据估计，与灭鼠相比，人类中乙酸烯丙雌酚的清除速度较慢。使用具有人源化肝脏的嵌合TK-NOG小鼠评估了乙酸美仑孕酮在人体内的分布。结果表明，简化的PBPK建模与体外和体内实验以及文献资源相结合的有用性，以及未来对使用另一个自下而上系统进行完整PBPK建模进行估算的兴趣。该模型还可用于风险评估和模拟因暴露于低剂量醋酸美仑孕酮和相关化合物而产生的血浆浓度。

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