Qiu Fiona, Habgood Mark D, Huang Yifan, Dziegielewska Katarzyna M, Toll Sam, Schneider-Futschik Elena K
Department of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
Department of Biochemistry & Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
J Cyst Fibros. 2021 Sep;20(5):857-864. doi: 10.1016/j.jcf.2021.06.005. Epub 2021 Jun 27.
The potential effects of ivacaftor during pregnancy and breastfeeding on the offspring are still unknown. This study aimed to investigate pre-/postnatal age-related entry into the brain and lungs and transfer of maternally administered drug by the placental and via the milk.
In acute experiments Sprague Dawley rats at embryonic day (E) 19, postnatal days (P) 4, 9, 16, and adult were administered an intraperitoneal injection of ivacaftor (40 mg/kg) traced with [3H] ivacaftor. To determine tissue entry, plasma, cerebrospinal fluid (CSF), lungs and brains were collected, and radioactivity measured using liquid scintillation counting. For long term experiments pregnant dams were orally treated at 25 mg/kg/day for 7 days and pups collected at E19. For postnatal pups, dams received treatment for 7 or 14 days and pups were collected at P6, 9, 13 and 16. To estimate placental and milk transfer concentration of ivacaftor in pup & maternal plasma was determined by liquid chromatography-mass spectrometry.
At all ages, entry of ivacaftor into lungs, following either acute or prolonged exposure, was much higher than into brain & CSF. Brain entry appeared higher at earlier ages. Transfer across the placenta and breast milk. was estimated to be around ~40% of maternal plasma.
Fetal and postnatal rats were exposed to maternally administered ivacaftor via placental and milk transfer. Preferential entry in the lungs at all ages suggests the possibility that exposing CF babies to maternally administered ivacaftor could be beneficial for limiting progression of CF pathology in early development.
依伐卡托在孕期和哺乳期对后代的潜在影响尚不清楚。本研究旨在调查产前/产后不同年龄阶段依伐卡托进入脑和肺的情况，以及母体给药后药物通过胎盘和乳汁的转运情况。
在急性实验中，给胚胎期第19天（E19）、出生后第4天（P4）、第9天、第16天的斯普拉格-道利大鼠及成年大鼠腹腔注射用[³H]依伐卡托标记的依伐卡托（40mg/kg）。为确定组织摄取情况，收集血浆、脑脊液（CSF）、肺和脑，并使用液体闪烁计数法测量放射性。在长期实验中，怀孕母鼠以25mg/kg/天的剂量口服给药7天，并在E19收集幼崽。对于出生后的幼崽，母鼠接受7天或14天的治疗，并在P6、P9、P13和P16收集幼崽。通过液相色谱-质谱法测定幼崽和母体血浆中依伐卡托的胎盘和乳汁转运浓度。
在所有年龄段，无论是急性暴露还是长期暴露后，依伐卡托进入肺的量都远高于进入脑和脑脊液的量。脑摄取在较早年龄似乎更高。经胎盘和母乳的转运估计约为母体血浆的40%。
胎儿和出生后的大鼠通过胎盘和乳汁转运接触母体给予的依伐卡托。在所有年龄段依伐卡托优先进入肺，这表明让患有囊性纤维化（CF）的婴儿接触母体给予的依伐卡托可能有利于限制CF病理在早期发育中的进展。
