TY - JOUR
T1 - First‐Pass CYP3A‐Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates
AU - Brussee, Janneke M.
AU - Yu, Huixin
AU - Krekels, Elke H. J.
AU - Roos, Berend de
AU - Brill, Margreke J. E.
AU - van den Anker, Johannes N.
AU - Rostami-Hodjegan, Amin
AU - Wildt, Saskia N. de
AU - Knibbe, Catherijne A.J.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1002/psp4.12295
DO - 10.1002/psp4.12295
M3 - Article
VL - 7
SP - 374
EP - 383
JO - CPT: Pharmacometrics and Systems Pharmacology
JF - CPT: Pharmacometrics and Systems Pharmacology
ER -