Pharmacological testing of therapeutics using normothermic machine perfusion: A pilot study of 2,4-dinitrophenol delivery to steatotic human livers.
Pharmacological testing of therapeutics using normothermic machine perfusion: A pilot study of 2,4-dinitrophenol delivery to steatotic human livers.
复制标题
使用常温机器灌注进行治疗的药理学测试：2,4-二硝基苯酚递送至脂肪变性人类肝脏的初步研究。
DOI：
10.1111/aor.14309
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发表时间：
2022
影响因子：
2.4
通讯作者：
Tingle SJ
中科院分区：
文献类型：
--
作者：
Tingle SJ
常温机器灌注（NMP）为药物输送提供了一个平台。然而，在NMP期间递送的治疗剂的药理学考虑几乎没有报道。我们的目的是证明NMP作为药理学测试的平台的能力，使用增加代谢的药物（2，4-二硝基苯酚; DNP）作为一个例子therapeutic.MethodsWe进行了25小时的NMP对人类肝脏已下降移植由于脂肪变性（n= 7）。三个肝脏接受了DNP丸，三个是控制，和一个接受了DNP infusation.ResultsToxicity研究显示DNP交付是安全的，没有肝毒性作用。在DNP组中，肝表面温度升高（p= 0.046），但没有肝脏出现DNP体内毒性机制--肝脏肥厚。药代动力学研究显示DNP消除具有一级动力学和7.7小时半衰期（95% CI = 5.1-15.9小时）。胆汁中DNP的清除率可忽略不计。正如预期的那样，DNP显著增加了耗氧量（p= 0.023）;这种增加与灌注液DNP浓度密切相关（r2= 0.975;p= 0.002），并且随着DNP被肝脏消除，这种作用消失。使用我们的药代动力学数据计算的DNP输注速率，成功地维持灌注液DNP concentration.DiscussionDetailed药理学测试可以在NMP期间进行。我们的治疗药物（DNP）可被离体肝脏迅速消除，这意味着代谢增加的药物效应只是短暂的。这证明了在NMP期间递送治疗剂时评估药代动力学的重要性，特别是对于在药物消除中具有既定作用的器官的延长灌注。需要进行严格的药理学测试，以释放NMP作为临床药物递送平台的潜力。
IntroductionNormothermic machine perfusion (NMP) provides a platform for drug‐delivery. However, pharmacological considerations for therapeutics delivered during NMP are scarcely reported. We aimed to demonstrate the ability of NMP as a platform for pharmacological testing, using a drug which increases metabolism (2,4‐dinitrophenol; DNP) as an example therapeutic.MethodsWe performed 25 h of NMP on human livers which had been declined for transplant due to steatosis (n= 7). Three livers received a DNP bolus, three were controls, and one received a DNP infusion.ResultsToxicity studies revealed DNP delivery was safe, without hepatotoxic effects. The liver surface temperature was increased in the DNP group (p= 0.046), but no livers suffered hyperthermia—the mechanism of DNP toxicity in vivo. Pharmacokinetic studies revealed DNP elimination with first‐order kinetics and 7.7 h half‐life (95% CI = 5.1–15.9 hrs). The clearance of DNP in bile was negligible. As expected, DNP significantly increased oxygen consumption (p= 0.023); this increase was closely correlated with perfusate DNP concentration (r2= 0.975;p= 0.002) and the effect was lost as DNP was eliminated by the liver. A DNP infusion rate, calculated using our pharmacokinetic data, successfully maintained perfusate DNP concentration.DiscussionDetailed pharmacological testing can be performed during NMP. Our therapeutic (DNP) is rapidly eliminated by the ex vivo liver, meaning the drug effect of increased metabolism is only transient. This demonstrates the importance of assessing pharmacokinetics when delivering therapeutics during NMP, especially for prolonged perfusion of organs with established roles in drug elimination. Rigorous pharmacological testing is needed to unlock the potential of NMP as a clinical drug‐delivery platform.