UGT2B15 单个核酸多态性减少了人类的达比加酸葡萄化物形成
Jin-Woo Park1,2,3, Jong-Min Kim1, Young Yoon Bang1
1Department of Clinical Pharmacology and Toxicology, Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
Frontiers in pharmacology
|January 24, 2025
概括
在UGT2B15的遗传变异影响达比加的药理动力学和新陈代谢在健康的男性. 这项研究突出了UGT2B15多形态如何影响达比加的葡萄化和药物暴露.
科学领域:
- 药物基因组学 药物基因组学
- 药物新陈代谢 药物新陈代谢
- 临床药理学 临床药理学
背景情况:
- 达比加特兰乙酸 (DABE) 是一种直接的血栓抑制剂,对于预防心房中风至关重要.
- 遗传变异,特别是UGT2B15多态变异对DABE代谢的影响需要进一步研究.
- 了解这些遗传影响是优化达比加特兰治疗的关键.
研究的目的:
- 调查UGT2B15,ABCB1和CES1遗传多态性对达比加特兰 (DAB) 和其酸葡萄糖化物代谢物的药理学的影响.
- 阐明UGT2B15在DAB糖化中的作用及其随后的药理动力学概况.
- 在健康的男性群体中评估这些多形态的临床相关性.
主要方法:
- 对124名健康男性进行UGT2B15,ABCB1和CES1多态的基因定型.
- 一次150毫克的DABE剂量管理和血采样.
- 使用LC-MS/MS量化总和自由DAB和达比加酸葡萄化物 (DABG),然后进行非分区性药理动力学分析.
主要成果:
- UGT2B15 c.253G>T多态性显著改变了自由DAB的药理动力学,特别是在TT基因型中显著降低了Tmax和口服清除.
- 与GT和TT基因型相比,GG基因型的DABGCmax和AUCall显著更高.
- GG和GT基因型与TT基因型相比,Cmax和AUCall的代谢物对母体比率显著更高,表明改变了葡萄糖化.
- ABCB1和CES1的多态性对DAB或DABG的药理动力学没有显著影响.
结论:
- UGT2B15的多态性与达比加糖化和药理动力学的变化有显著的关联.
- UGT2B15 c.253G>T多态影响达比加特兰暴露和代谢.
- 这些发现强调了对达比加特兰治疗的药物遗传学考虑的重要性.
相关概念视频
Phase II Reactions: Glucuronidation
261
Glucuronidation, a pivotal phase II biotransformation process, involves the coupling of glucuronic acid to a drug or xenobiotic. Given its widespread occurrence and critical role in drug metabolism, it's considered the most crucial phase II reaction. It enhances the water solubility of substances, aiding their expulsion from the body. The driving force behind these reactions is a group of enzymes known as UDP-glucuronosyltransferases (UGTs). UGTs facilitate the transfer of a glucuronic acid...
261
Drug Metabolism: Phase II Reactions
3.6K
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...
3.6K
Factors Affecting Drug Biotransformation: Biological
104
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...
104
Drug Distribution: Plasma Protein Binding
4.8K
Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the bound fraction. Acidic drugs form large, inactive complexes by reversibly binding to plasma albumin, which prevents them from diffusing across biological barriers. These drug-protein complexes act as reservoirs for the drugs. As the concentration of unbound drugs decreases, these complexes quickly dissociate to release the free drug, maintaining...
4.8K
Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance
78
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...
78
Anticoagulant Drugs: Vitamin K Antagonists and Direct Oral Anticoagulants
1.1K
Oral anticoagulants are vital tools in preventing and treating blood clotting disorders. This diverse class of medications can be categorized as vitamin K antagonists, exemplified by warfarin, and direct thrombin inhibitors (DTIs), such as dabigatran, as well as factor Xa inhibitors, including rivaroxaban.
Warfarin, a prominent vitamin K antagonist family member, exerts its effect by inhibiting the enzyme VKORC1 (vitamin K epoxide reductase complex 1). By hindering this enzyme, warfarin...
Warfarin, a prominent vitamin K antagonist family member, exerts its effect by inhibiting the enzyme VKORC1 (vitamin K epoxide reductase complex 1). By hindering this enzyme, warfarin...
1.1K


