In Vitro Ciclopirox Glucuronidation in Liver Microsomes from Humans and Various Experimental Animals.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Wenjing Li, Yufan Xue, Feng Zhang, Ling Xiao, Zhu Huang, Wenjuan Li, Liangliang Zhu, Guangbo Ge
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引用次数: 0

Abstract

Background and objective: Ciclopirox is a widely used antifungal drug, redisposition of which has drawn increasing attentions due to multiple promising activities. The drug undergoes extensive glucuronidation, which acts as a major obstacle in the ongoing novel application and still remains poorly understood. The current study aims to phenotype ciclopirox glucuronidation pathway and as well to decipher the related species differences.

Methods: Ciclopirox glucuronidation was investigated in liver microsomes from humans (HLM) and various experimental animals. Assays with recombinant uridine diphosphate glucuronosyltransferases (UGTs), enzyme kinetic analyses and selective inhibitors were used to determine the role of individual UGTs in ciclopirox glucuronidation.

Results: HLM is highly active in ciclopirox glucuronidation with Michaelis-Menten constant (Km), maximum velocity (Vmax), and intrinsic clearance (CLint) values of 139 μM, 7.89 nmol/min/mg, and 56 μL/min/mg, respectively. UGT1A9 displays by far the highest activity, whereas several other isoforms (UGT1A6, UGT1A7, and UGT1A8) catalyze formation of traced glucuronides. Further kinetic analysis demonstrates that UGT1A9 has a closed Km value (167 μM) to HLM. UGT1A9 selective inhibitor (magnolol) can potently inhibit ciclopirox glucuronidation in HLM with the IC50 value of 0.12 μM. The reaction displays remarkable differences across liver microsomes from mice, rats, cynomolgus monkey, minipig, and beagle dog, with the CLint values in the range of 26-369 μL/min/mg. In addition, ciclopirox glucuronidation activities of experimental animals' liver microsomes were less sensitive to magnolol than that of HLM.

Conclusions: Ciclopirox glucuronidation displays remarkable species differences with UGT1A9 as a dominant contributor in humans. It is suggested that the pharmacological or toxicological effects of ciclopirox may be UGT1A9 and species dependent.

Abstract Image

人类和各种实验动物肝脏微粒体中的体外环吡酮胺葡萄糖醛酸化反应
背景和目的:环吡酮胺是一种广泛使用的抗真菌药物,由于其具有多种有前途的活性,其再处置已引起越来越多的关注。该药物会发生广泛的葡萄糖醛酸化反应,这是目前新型药物应用中的一个主要障碍,而且人们对这一问题仍然知之甚少。本研究旨在对环吡酮胺葡萄糖醛酸化途径进行表型分析,并解读相关物种的差异:方法:研究了环吡酮胺在人类(HLM)和各种实验动物肝脏微粒体中的葡萄糖醛酸化作用。使用重组二磷酸尿苷葡萄糖醛酸转移酶(UGTs)、酶动力学分析和选择性抑制剂来确定单个 UGTs 在环吡酮胺葡萄糖醛酸化过程中的作用:结果:HLM 在环吡酮胺葡萄糖醛酸化过程中活性很高,其迈克尔斯-门顿常数(Km)、最大速度(Vmax)和固有清除率(CLint)值分别为 139 μM、7.89 nmol/min/mg 和 56 μL/min/mg。到目前为止,UGT1A9 的活性最高,而其他几种异构体(UGT1A6、UGT1A7 和 UGT1A8)则能催化形成痕量葡萄糖醛酸。进一步的动力学分析表明,UGT1A9 对 HLM 的 Km 值(167 μM)是封闭的。UGT1A9 选择性抑制剂(magnolol)能有效抑制环吡酮胺在 HLM 中的葡萄糖醛酸化反应,其 IC50 值为 0.12 μM。该反应在小鼠、大鼠、金丝猴、迷你猪和小猎犬的肝脏微粒体中表现出明显的差异,CLint 值在 26-369 μL/min/mg 之间。此外,与 HLM 相比,实验动物肝脏微粒体的环吡酮胺葡萄糖醛酸化活性对 magnolol 的敏感性较低:结论:环吡酮胺的葡萄糖醛酸化作用显示出显著的物种差异,UGT1A9 是人类的主要贡献者。这表明环吡酮胺的药理或毒理效应可能与 UGT1A9 和物种有关。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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