氧化chloroquine的微体代谢的物种差异
Guilin Wei1, Chaohua Yan2, Liwei Zou2
1Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China; School of Chemical Engineering, Ocean and Life Sciences, Dalian University of Technology, Panjin 124221, China.
概括
化 (HCQ) 的新陈代谢在物种之间有很大差异,与动物模型相比,在人类中发现了不同的途径和关键酶. 这项研究有助于选择适合药物开发的动物模型,并了解潜在的药物相互作用.
科学领域:
- 药理学 药理学是指药理学的学科.
- 药物新陈代谢 药物新陈代谢
- 毒理学 毒理学 毒理学
背景情况:
- 氧化 (HCQ) 广泛用于疟疾和自身免疫性疾病.
- 涉及HCQ的药物相互作用 (DDI),特别是与细胞染色体P450 (CYP) 酶的相互作用,是令人担忧的.
- 对于HCQ的物种特异性药理动力学和新陈代谢尚不清楚.
研究的目的:
- 在人类肝脏显微体 (HLM) 和临床前动物模型中比较分析HCQ代谢和药理动力学.
- 确定负责跨物种HCQ代谢的关键CYP酶.
- 为了阐明HCQ的特定物种代谢途径.
主要方法:
- 使用人类,小鼠,老鼠,狗和猪的肝脏显微体对HCQ代谢的比较分析.
- 代谢物分析,以确定主要和独特的代谢物.
- 在HLM中使用选择性CYP异型抑制剂的酶抑制研究.
主要成果:
- 在所有测试物种中,单氧化代谢物M5是常见的.
- 代谢物M4和M6仅在猪肝显微体中产生.
- 人类HCQ代谢涉及CYP2D6,CYP2C8,CYP3A4和CYP1A1,有不同的途径和显著的基质抑制.
- 代谢途径和关键酶在人类和动物模型之间存在显著差异.
结论:
- 人类的HCQ代谢与临床前物种中观察到的不同.
- 了解这些物种差异对于选择适合HCQ研究的动物模型至关重要.
- 这项研究为评估HCQ体内行为及其在组合疗法中的潜在用途提供了洞察力.
相关概念视频
Factors Affecting Drug Biotransformation: Biological
79
Biological factors significantly impact drug metabolism, influencing drug clearance, efficacy, and potential toxicity.
Species differences: Variations in enzyme systems across species can cause disparities in drug metabolism. For instance, humans may metabolize certain drugs faster than rodents, altering therapeutic effects.
Strain differences: Genetic variations within a species can result in differing enzyme activity, impacting drug response and toxicity. For example, some mouse strains may...
Species differences: Variations in enzyme systems across species can cause disparities in drug metabolism. For instance, humans may metabolize certain drugs faster than rodents, altering therapeutic effects.
Strain differences: Genetic variations within a species can result in differing enzyme activity, impacting drug response and toxicity. For example, some mouse strains may...
79
Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance
48
The elimination half-life and drug clearance of drugs following nonlinear kinetics can vary with dosage. The Michaelis-Menten parameters and drug concentration influence these factors. As the dose increases, the elimination half-life tends to lengthen, resulting in a reduction in clearance and a disproportionately larger area under the curve. The total clearance can be derived from the Michaelis-Menten equation for drugs following a one-compartment model.
A study on guinea pigs examined the...
A study on guinea pigs examined the...
48
Hepatic Drug Clearance: Role of Transporters
26
In the liver and bile canaliculi, influx and efflux transporters modification can influence intrinsic clearance. Transporters play a significant role in moving drugs within liver cells. Elaborate models, such as the Biopharmaceutical Classification System (BCS), are essential to relate transporters to drug disposition. This system categorizes drugs into four classes based on solubility and permeability, providing insights into elimination routes and the effects of transporters following oral...
26
Drug Metabolism: Phase II Reactions
3.4K
Phase II reactions are essential for the detoxification and elimination of drugs from the body. These reactions involve the conjugation of parent drugs or their phase I metabolites with endogenous molecules, resulting in more hydrophilic drug conjugates. The primary conjugation reactions in this phase are sulfation and glucuronidation. Both sulfation and glucuronidation typically produce biologically inactive metabolites. However, in some cases involving prodrugs, active metabolites may be...
3.4K
Hepatic Drug Clearance: Effect of Protein Binding
116
Hepatic clearance is influenced by protein binding based on the drug's extraction ratio. Drugs with high extraction ratios are considered flow-limited and remain unaffected by protein binding during hepatic clearance. On the other hand, drugs with low extraction ratios may be impacted by plasma protein binding, although the extent of this influence depends on the fraction of the drug bound.
For low-extraction-ratio drugs that are less than 80% protein-bound, minor changes in protein binding...
For low-extraction-ratio drugs that are less than 80% protein-bound, minor changes in protein binding...
116
Factors Affecting Renal Clearance: Drug's Physicochemical Properties and Plasma Levels
139
Renal clearance of a drug is influenced by various factors, including its physicochemical properties and plasma levels. These factors play a significant role in determining how efficiently the kidneys eliminate a drug.
One important factor is the drug's molecular size. The kidneys readily excrete smaller molecules below 300 Daltons (Da). On the other hand, molecules weighing between 300 and 500 Da are excreted through both urine and bile. Larger molecules above 500 Da tend to be excreted...
One important factor is the drug's molecular size. The kidneys readily excrete smaller molecules below 300 Daltons (Da). On the other hand, molecules weighing between 300 and 500 Da are excreted through both urine and bile. Larger molecules above 500 Da tend to be excreted...
139


