3,3′-二吲哚基甲烷在人体口服给药后表现出显着的代谢,Drug Metabolism and Disposition

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3,3′-二吲哚基甲烷在人体口服给药后表现出显着的代谢
Drug Metabolism and Disposition ( IF 4.4 ) Pub Date : 2021-08-01 , DOI: 10.1124/dmd.120.000346
Monica L Vermillion Maier ₁ , Lisbeth K Siddens ₁ , Sandra L Uesugi ₁ , Jaewoo Choi ₁ , Scott W Leonard ₁ , Jamie M Pennington ₁ , Susan C Tilton ₁ , Jordan N Smith ₁ , Emily Ho ₁ , H H Sherry Chow ₁ , Bach D Nguyen ₁ , Siva K Kolluri ₁ , David E Williams ₂

Affiliation

3,3'-二吲哚甲烷 (DIM) 是一种从十字花科蔬菜中提取的主要植物化学物质，也是一种膳食补充剂。在临床前模型中，DIM 是一种有效的癌症化学预防剂，并已在多项临床试验中进行了研究。先前的临床前和临床模型药代动力学研究尚未报道口服给药后血浆或尿液中的 DIM 代谢物，并且 DIM 对靶组织的药理作用被认为仅通过母体化合物产生。七名受试者（6 名男性和 1 名女性）年龄范围为 26-65 岁，在研究之前和研究期间限制十字花科蔬菜饮食，每天晚上服用 2 粒 BioResponse DIM 150 毫克胶囊（45.3 毫克 DIM/胶囊）一周，在第一次抽血的早晨服用最后一剂。对 48 小时内收集的血浆和尿液进行完整的时间过程，并通过 UPLC-MS/MS 进行分析。除母体 DIM 外，血浆和尿液中还存在两种单羟基化代谢物和 1 种二羟基化代谢物及其硫酸盐和葡萄糖醛酸结合物。本文报告的结果表明存在显着的 1 相和 2 相代谢，并且与之前在啮齿动物和人类中进行的药代动力学研究不同，后者报告口服给药后仅存在母体 DIM。3-((1 H-吲哚-3-基)甲基)吲哚啉-2-酮被鉴定为单羟基化产物之一，在异生素反应元件-荧光素酶报告基因中进行测试时，作为芳基烃受体激动剂表现出更大的效力和功效使用 Hepa1 细胞进行测定。除了竞争性植物化学药物不良反应外，其他代谢物可能表现出药理活性，凸显了进一步表征人类 DIM 代谢的重要性。

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3,3′-Diindolylmethane Exhibits Significant Metabolism after Oral Dosing in Humans

3,3′-Diindolylmethane (DIM), a major phytochemical derived from ingestion of cruciferous vegetables, is also a dietary supplement. In preclinical models, DIM is an effective cancer chemopreventive agent and has been studied in a number of clinical trials. Previous pharmacokinetic studies in preclinical and clinical models have not reported DIM metabolites in plasma or urine after oral dosing, and the pharmacological actions of DIM on target tissues is assumed to be solely via the parent compound. Seven subjects (6 males and 1 female) ranging from 26–65 years of age, on a cruciferous vegetable-restricted diet prior to and during the study, took 2 BioResponse DIM 150-mg capsules (45.3 mg DIM/capsule) every evening for one week with a final dose the morning of the first blood draw. A complete time course was performed with plasma and urine collected over 48 hours and analyzed by UPLC-MS/MS. In addition to parent DIM, two monohydroxylated metabolites and 1 dihydroxylated metabolite, along with their sulfate and glucuronide conjugates, were present in both plasma and urine. Results reported here are indicative of significant phase 1 and phase 2 metabolism and differ from previous pharmacokinetic studies in rodents and humans, which reported only parent DIM present after oral administration. 3-((1H-indole-3-yl)methyl)indolin-2-one, identified as one of the monohydroxylated products, exhibited greater potency and efficacy as an aryl hydrocarbon receptor agonist when tested in a xenobiotic response element-luciferase reporter assay using Hepa1 cells. In addition to competitive phytochemical-drug adverse reactions, additional metabolites may exhibit pharmacological activity highlighting the importance of further characterization of DIM metabolism in humans.

更新日期：2021-08-24

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