Entry of cystic fibrosis transmembrane conductance potentiator ivacaftor into the developing brain and lung |
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| Affiliation: | 1. Halo Research Group, Queen''s University Belfast, Belfast, UK;2. Wellcome-Wolfson Institute for Experimental Medicine. School of Medicine, Dentistry and Biomedical Sciences Queen''s University Belfast, Belfast, UK;3. School of Pharmacy, Queen''s University Belfast, Belfast, UK;4. Cork Centre for Cystic Fibrosis, Cork University Hospital, University College Cork, Ireland;5. HRB Clinical Research Facility, University College Cork, Cork, Ireland;6. Department of Medicine, Cork University Hospital, Wilton, Cork, Ireland;1. Department of Genetic Medicine, Johns Hopkins University (JHU), Baltimore, MD, 21205, USA;2. University of North Carolina at Chapel Hill (UNC), Chapel Hill, NC, 27599, USA;1. The Ohio State University, School of Health and Rehabilitation Sciences, 453 W. 10th Avenue, Columbus, OH, 43210, USA;2. Nationwide Children''s Hospital, Division of Gastroenterology, Hepatology, and Nutrition, 700 Children''s Drive, Columbus, OH 43205, USA;3. The Ohio State University Wexner Medical Center, Division of Gastroenterology, Hepatology, and Nutrition, 2nd Floor Doan Office Tower, 395 W. 12th Ave., Columbus, OH 43210-1228, USA;4. Nationwide Children''s Hospital, Division of Pulmonary Medicine, 700 Children''s Drive, Columbus, OH 43205, USA;1. Division of Biostatistics & Epidemiology, Cincinnati Children''s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA;2. Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;3. Department of Pediatrics, University of Cincinnati, MLC 0555, 3230 Eden Ave, Cincinnati, OH 45267, USA;4. Department of Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, the Netherlands;5. Division of Pulmonary Medicine, Cincinnati Children''s Hospital Medical Center, MLC 2021, 3333 Burnet Ave, Cincinnati, OH 45229, USA;6. Cystic Fibrosis Foundation, 4550 Montgomery Ave, Suite 1100N, Bethesda, MD 20814, USA;7. Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, MCLM 706, 1918 University Blvd, Birmingham, AL 35294, USA;8. Department of Medicine, University of Alabama at Birmingham, THT 422, 1900 University Blvd, Birmingham, AL 35294, USA |
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| Abstract: | BackgroundThe 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.MethodsIn 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.ResultsAt 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.ConclusionsFetal 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. |
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