Toxicology and applied pharmacology · 2023
Intra-amniotic sildenafil administration in rabbits: Safety, pharmacokinetics, organ distribution and histologic evaluation.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Yoshida Shiho, Kreger Alexander M, Shaik Imam H, West Raymond E, Venkataramanan Raman, Gittes George K
Аннотация
BACKGROUND: The effectiveness of sildenafil in the management of pulmonary hypertension in congenital diaphragmatic hernia (CDH) has been reported but has not been systematically evaluated. Our studies have also demonstrated that intra-amniotic (IA) sildenafil administration improves pulmonary hypertension in CDH.
METHODS: We evaluated the pharmacokinetics of sildenafil after IA administration in pregnant rabbits. Following maternal laparotomy, fetuses received IA injection of 0.8 mg of sildenafil. Maternal blood, amniotic fluid, and fetal tissues were collected at various time points. The concentrations of sildenafil and its major metabolite in samples were analyzed by liquid chromatography-mass spectrometry. To assess organ toxicity, 7 days after IA sildenafil administration, fetal organs were examined histologically.
RESULTS: After IA dosing, sildenafil was absorbed quickly with an absorption half-life of 0.03-0.07 h into the fetal organs. All the organs showed a maximum concentration within 1 h and the disposition half-life ranged from 0.56 to 0.73 h. Most of the sildenafil was eliminated from both mothers and fetuses within 24 h after a single dose. There was no histological evidence of organ toxicity in the fetuses after a single dose of IA administration of sildenafil.
CONCLUSION: IA sildenafil is rapidly absorbed into the fetus, distributes into the mother, and is eliminated by the mother without accumulation or fetal organ toxicity. This study confirms the feasibility and the safety of IA administration of sildenafil and enables future applications in the treatment of CDH fetuses.
METHODS: We evaluated the pharmacokinetics of sildenafil after IA administration in pregnant rabbits. Following maternal laparotomy, fetuses received IA injection of 0.8 mg of sildenafil. Maternal blood, amniotic fluid, and fetal tissues were collected at various time points. The concentrations of sildenafil and its major metabolite in samples were analyzed by liquid chromatography-mass spectrometry. To assess organ toxicity, 7 days after IA sildenafil administration, fetal organs were examined histologically.
RESULTS: After IA dosing, sildenafil was absorbed quickly with an absorption half-life of 0.03-0.07 h into the fetal organs. All the organs showed a maximum concentration within 1 h and the disposition half-life ranged from 0.56 to 0.73 h. Most of the sildenafil was eliminated from both mothers and fetuses within 24 h after a single dose. There was no histological evidence of organ toxicity in the fetuses after a single dose of IA administration of sildenafil.
CONCLUSION: IA sildenafil is rapidly absorbed into the fetus, distributes into the mother, and is eliminated by the mother without accumulation or fetal organ toxicity. This study confirms the feasibility and the safety of IA administration of sildenafil and enables future applications in the treatment of CDH fetuses.