First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates
Autor: | Johannes N. van den Anker, Berend de Roos, Saskia N. de Wildt, Huixin Yu, Margreke J. E. Brill, Amin Rostami-Hodjegan, Catherijne A. J. Knibbe, Janneke M. Brussee, Elke H. J. Krekels |
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Rok vydání: | 2018 |
Předmět: |
medicine.medical_specialty
education.field_of_study biology CYP3A business.industry Population Cytochrome P450 Gestational age Metabolism 030226 pharmacology & pharmacy Gastroenterology Bioavailability 03 medical and health sciences 0302 clinical medicine Pharmacokinetics 030220 oncology & carcinogenesis Modeling and Simulation Internal medicine medicine biology.protein Midazolam Pharmacology (medical) education business medicine.drug |
Zdroj: | CPT: Pharmacometrics & Systems Pharmacology. 7:374-383 |
ISSN: | 2163-8306 |
DOI: | 10.1002/psp4.12295 |
Popis: | To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1-OH-midazolam concentrations from 37 preterm neonates (gestational age 26-34 weeks) receiving midazolam orally and/or via a 30-minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0.0196 and 6.7 L/h, respectively). This results in a highly variable and high total oral bioavailability of 92.1% (range, 67-95%) in preterm neonates, whereas this is around 30% in adults. This approach in which intestinal and hepatic clearance were separately estimated shows that the high bioavailability in preterm neonates is explained by, likely age-related, low CYP3A activity in the liver and even lower CYP3A activity in the gut wall. |
Databáze: | OpenAIRE |
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