Dolutegravir metabolism: impact of genetic variations on uridine diphosphate glucuronosyltransferase subfamilies.

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY Xenobiotica Pub Date : 2025-01-20 DOI:10.1080/00498254.2025.2453983

Kouji Tagawa, Yoshihiro Maruo

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Abstract

Dolutegravir (DTG) is a key drug used to treat human immunodeficiency virus type-1 (HIV-1) infections. Adverse events (AEs) of DTG treatment, including headache, anxiety, depression, insomnia, and abnormal dreams, are influenced by sex, body weight, age, and serum bilirubin levels. DTG is mainly metabolised by members of the uridine diphosphate glucuronosyltransferase 1A subfamilies (UGT1As), especially UGT1A1.Some studies suggest a relationship between UGT1A1 variants and AEs. The aim of this study was to identify UGT1A isoforms that exhibit DTG glucuronidation activity and determine the relationship between UGT1A variants and DTG glucuronidation in vitro.UGT1A1, UGT1A3, UGT1A9, and UGT1A10 exhibited DTG glucuronidation activity, of which UGT1A1 was the most active. Furthermore, variants of these isoforms showed decreased DTG glucuronidation activity. The different variants of UGT1As, such as UGT1A1.6, UGT1A1.7, UGT1A1.35, UGT1A1.63, UGT1A3.5, UGT1A9.2, UGT1A10M59I, and UGT1A10T202I, showed reduced glucuronidation activity towards DTG in comparison with the wild-type UGT1As.This study elucidates the relationship between UGT1A variants and the levels of glucuronidation associated with each variant.Checking for UGT1As may be helpful in predicting potential toxicities and adverse effects related to DTG treatment.

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多替格拉韦代谢：遗传变异对尿苷二磷酸葡萄糖醛酸转移酶亚家族的影响。

Dolutegravir （DTG）是治疗人类免疫缺陷病毒1型（HIV-1）感染的关键药物。DTG治疗的不良事件（ae），包括头痛、焦虑、抑郁、失眠和梦异常，受性别、体重、年龄和血清胆红素水平的影响。二甘油三酯主要由尿苷二磷酸葡萄糖醛酸转移酶1A亚家族（UGT1As）成员代谢，尤其是UGT1A1。一些研究表明UGT1A1变异与ae之间存在关系。本研究的目的是鉴定具有DTG糖醛酸化活性的UGT1A亚型，并确定UGT1A变体与体外DTG糖醛酸化之间的关系。UGT1A1、UGT1A3、UGT1A9和UGT1A10表现出DTG糖醛酸化活性，其中UGT1A1活性最强。此外，这些异构体的变体显示DTG糖醛酸化活性降低。UGT1As的不同变异体UGT1A1.6、UGT1A1.7、UGT1A1.35、UGT1A1.63、UGT1A3.5、UGT1A9.2、UGT1A10M59I和UGT1A10T202I对DTG的糖醛酸化活性均低于野生型UGT1As。本研究阐明了UGT1A变体与每种变体相关的糖醛酸化水平之间的关系。检查ugt1a可能有助于预测与DTG治疗相关的潜在毒性和不良反应。

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来源期刊

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

审稿时长

2 months

期刊介绍： Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology