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
Rok vydání: 2018
Předmět:
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
Nepřihlášeným uživatelům se plný text nezobrazuje