Placental transfer of tofacitinib in the ex vivo dual-side human placenta perfusion model

IF 2.9 Q2 TOXICOLOGY Current Research in Toxicology Pub Date : 2024-01-01 DOI:10.1016/j.crtox.2024.100149
Gaby A.M. Eliesen , Milou Fransen , Hedwig van Hove , Petra H.H. van den Broek , Rick Greupink
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Abstract

Tofacitinib is a small molecule Janus kinase (JAK) inhibitor, introduced to the European market in 2017, for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. In the treatment of women with autoimmune diseases, pregnancy is a relevant issue, as such diseases typically affect women in their reproductive years. Currently, there is limited data on the use of tofacitinib during pregnancy. To estimate the extent of placental transfer in the absence of clinical data, we conducted ex vivo dual-side perfused human placental cotyledon perfusions. Term placentas were perfused for 180 min with tofacitinib (100 nM, added to the maternal circuit) in a closed-closed configuration. At the end of the perfusions, drug concentrations in the maternal and fetal reservoirs were near equilibrium, at 35.6 ± 5.5 and 24.8 ± 4.7 nM, respectively. Transfer of tofacitinib was similar to that observed for the passive diffusion marker antipyrine (100 µg/mL, added to the maternal reservoir). Final antipyrine maternal and fetal concentrations amounted to 36.9 ± 3.0 and 36.7 ± 1.3 µg/mL, respectively. In conclusion, in the ex vivo perfused placenta tofacitinib traverses the placental barrier rapidly and extensively. This suggests that substantial fetal tofacitinib exposure will take place after maternal drug dosing.

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体内外双侧人体胎盘灌注模型中托法替尼的胎盘转移
托法替尼是一种小分子 Janus 激酶(JAK)抑制剂,于 2017 年引入欧洲市场,用于治疗类风湿性关节炎、银屑病关节炎和溃疡性结肠炎。在治疗患有自身免疫性疾病的妇女时,怀孕是一个相关问题,因为这类疾病通常会影响育龄期妇女。目前,有关怀孕期间使用托法替尼的数据有限。为了在缺乏临床数据的情况下估计胎盘转移的程度,我们进行了体外双侧灌注人胎盘子叶灌注。足月胎盘与托法替尼(100 nM,加入母体回路)以闭合配置灌注180分钟。灌注结束时,母体和胎儿储库中的药物浓度接近平衡,分别为 35.6 ± 5.5 和 24.8 ± 4.7 nM。托法替尼的转移与被动扩散标记物安替比林(100 µg/mL,加入母体储库)的转移相似。母体和胎儿的最终安替比林浓度分别为 36.9 ± 3.0 µg/mL 和 36.7 ± 1.3 µg/mL。总之,在体外灌注胎盘中,托法替尼能快速、广泛地穿过胎盘屏障。这表明胎儿在母体用药后会大量接触托法替尼。
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来源期刊
Current Research in Toxicology
Current Research in Toxicology Environmental Science-Health, Toxicology and Mutagenesis
CiteScore
4.70
自引率
3.00%
发文量
33
审稿时长
82 days
期刊最新文献
Editorial Board Contents Evaluation of the diphenyl herbicide, oxyfluorfen, for effects on thyroid hormones in the juvenile rat Ethylene dimethanesulfonate effects on gene promoter activities related to the endocrine function of immortalized Leydig cell lines R2C and MA-10 Placental transfer of tofacitinib in the ex vivo dual-side human placenta perfusion model
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