A close examination of BCRP's role in lactation and methods for predicting drug distribution into milk

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Caroline Sychterz, Hong Shen, Yueping Zhang, Michael Sinz, Amin Rostami-Hodjegan, Brian J. Schmidt, Lu Gaohua, Aleksandra Galetin
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Abstract

Breastfeeding is the most complete nutritional method of feeding infants, but several impediments affect the decision to breastfeed, including questions of drug safety for medications needed during lactation. Despite recent FDA guidance, few labels provide clear dosing advice during lactation. Physiologically based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms to fill gaps in the absence of extensive clinical studies and complement existing real-world data. For lactation-focused PBPK (Lact-PBPK) models, information on system parameters (e.g., expression of drug transporters in mammary epithelial cells) is sparse. The breast cancer resistance protein (BCRP) is expressed on the apical side of mammary epithelial cells where it actively transports drugs/substrates into milk (reported milk: plasma ratios range from 2 to 20). A critical review of BCRP and its role in lactation was conducted. Longitudinal changes in BCRP mRNA expression have been identified in women with a maximum reached around 5 months postpartum. Limited data are available on the ontogeny of BCRP in infant intestine; however, data indicate lower BCRP abundance in infants compared to adults. Current status of incorporation of drug transporter information in Lact-PBPK models to predict active secretion of drugs into breast milk and consequential exposure of breast-fed infants is discussed. In addition, this review highlights novel clinical tools for evaluation of BCRP activity, namely a potential non-invasive BCRP biomarker (riboflavin) and liquid biopsy that could be used to quantitatively elucidate the role of this transporter without the need for administration of drugs and to inform Lact-PBPK models.

Abstract Image

仔细研究 BCRP 在哺乳期的作用以及预测药物在乳汁中分布的方法。
母乳喂养是哺育婴儿最全面的营养方式,但母乳喂养的决定会受到一些障碍的影响,包括哺乳期所需药物的安全性问题。尽管美国食品及药物管理局(FDA)最近发布了指导意见,但很少有标签提供哺乳期用药的明确建议。基于生理学的药代动力学建模(PBPK)非常适合从机理上探索药代动力学和用药范例,以填补缺乏大量临床研究的空白,并补充现有的真实世界数据。对于以哺乳期为重点的 PBPK(Lact-PBPK)模型而言,有关系统参数(如药物转运体在乳腺上皮细胞中的表达)的信息非常稀少。乳腺癌抗性蛋白(BCRP)在乳腺上皮细胞顶端表达,它能积极地将药物/底物转运到乳汁中(报告的乳汁:血浆比率从 2 到 20 不等)。我们对 BCRP 及其在泌乳中的作用进行了深入研究。已发现妇女体内 BCRP mRNA 表达的纵向变化,在产后 5 个月左右达到最大值。有关婴儿肠道中 BCRP 的本体发生的数据有限;不过,数据表明婴儿体内 BCRP 的丰度低于成人。本综述讨论了将药物转运体信息纳入 Lact-PBPK 模型的现状,以预测药物在母乳中的活性分泌和母乳喂养婴儿的相应暴露。此外,本综述还强调了评估 BCRP 活性的新型临床工具,即潜在的非侵入性 BCRP 生物标记物(核黄素)和液体活检,可用于定量阐明该转运体的作用,而无需服用药物,并为 Lact-PBPK 模型提供信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
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