Ontogeny of midazolam glucuronidation in preterm infants.
OBJECTIVE
In preterm infants, the biotransformation of midazolam (M) to 1-OH-midazolam (OHM) by cytochrome P450 3A4 (CYP3A4) is developmentally immature, but it is currently unknown whether the glucuronidation of OHM to 1-OH-midazolam glucuronide (OHMG) is also decreased. The aim of our study was to investigate the urinary excretion of midazolam and its metabolites OHM and OHMG in preterm neonates following the intravenous (IV) or oral (PO) administration of a single M dose.


METHODS
Preterm infants (post-natal age 3-13 days, gestational age 26-34 4/7 weeks) scheduled to undergo a stressful procedure received a 30-min IV infusion (n = 15) or a PO bolus dose (n= 7) of 0.1 mg/kg midazolam. The percentage of midazolam dose excreted in the urine as M, OHM and OHMG up to 6 h post-dose was determined.


RESULTS
The median percentage of the midazolam dose excreted as M, OHM and OHMG in the urine during the 6-h interval after the IV infusion was 0.44% (range 0.02-1.39%), 0.04% (0.01-0.13%) and 1.57% (0.36-7.7%), respectively. After administration of the PO bolus dose, the median percentage of M, OHM and OHMG excreted in the urine was 0.11% (0.02-0.59%), 0.02% (0.00-0.10%) and 1.69% (0.58-7.31%), respectively. The proportion of the IV midazolam dose excreted as OHMG increased significantly with postconceptional age (r = 0.73, p < 0.05).


CONCLUSIONS
The glucuronidation of OHM appears immature in preterm infants less than 2 weeks of age. The observed increase in urinary excretion of OHMG with postconceptional age likely reflects the combined maturation of glucuronidation and renal function.
Department of Paediatrics and Paediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands. s.dewildt@erasmusmc.nl
Saskia N
SN
de Wildt
Greg L
GL
Kearns
Darryl J
DJ
Murry
Gideon
G
Koren
John N
JN
van den Anker
D000284:Administration, Oral; D000375:Aging; D001711:Biotransformation; D005260:Female; D020719:Glucuronides / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000378:metabolism*; D007275:Injections, Intravenous; D007668:Kidney / Q000254:growth & development; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D020719:Glucuronides; D008874:Midazolam