Scialli Anthony R, Bailey Graham, Beyer Bruce K, Bøgh Ingrid Brück, Breslin William J, Chen Connie L, DeLise Anthony M, Hui Julia Y, Moffat Graeme J, Stewart Jane, Thompson Kary E
Reproductive Toxicology Center and Scialli Consulting LLC, Washington DC, USA.
Janssen R&D, Beerse, Belgium.
Reprod Toxicol. 2015 Dec;58:213-21. doi: 10.1016/j.reprotox.2015.10.015. Epub 2015 Nov 3.
Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins. It is not known whether peptide products reach semen, but in general peptide medications are destroyed by vaginal peptidases, and conceptus exposure is predicted to be minimal. Theoretical exposure routes to pharmaceuticals that might result in exposure of the conceptus greater than that of maternal systemic exposures include direct access through the cervical canal, adsorption to sperm for carriage into the oocyte, and direct delivery from the vaginal veins or lymphatics to the uterine artery. There is some evidence for direct access to the uterus for progesterone, terbutaline, and danazol, but the evidence does not involve exposures during pregnancy in most instances. Studies in mice, rats, rabbits, and monkeys do not suggest that exposure to small molecule pharmaceuticals in semen imposes risks to the conceptus beyond those that can be predicted using modeling of systemic maternal exposure. Monoclonal antibody and peptide exposure in semen does not pose a significant risk to the conceptus.
小分子药物产品在精液中的浓度被假定与血浆中的浓度相似。这些小分子产品在人体中的暴露模型假设每日精液量为5毫升，且从阴道100%吸收，并通过母体体循环分布到胚胎。单克隆抗体药物在精液中的浓度约为血液中浓度的2%或更低，用于小分子的模型会高估胚胎接触免疫球蛋白的可能性。尚不清楚肽类产品是否会进入精液，但一般来说，肽类药物会被阴道肽酶破坏，预计胚胎接触量极小。可能导致胚胎接触量大于母体体循环接触量的药物理论暴露途径包括通过宫颈管直接进入、吸附于精子并带入卵母细胞，以及从阴道静脉或淋巴管直接输送至子宫动脉。有一些证据表明孕酮、特布他林和达那唑可直接进入子宫，但在大多数情况下，这些证据并不涉及孕期暴露。对小鼠、大鼠、兔子和猴子的研究表明，精液中小分子药物的暴露给胚胎带来的风险并不高于通过母体体循环暴露模型预测的风险。精液中的单克隆抗体和肽类暴露对胚胎不构成重大风险。
