Pharmacokinetics and metabolism of oral midazolam in preterm infants.
OBJECTIVE
To characterize the pharmacokinetics and metabolism of oral midazolam in 15 preterm infants.


METHODS
After an oral dose (0.1 mg kg(-1)), blood was drawn up to 24 h after administration. Midazolam and 1-OH-midazolam concentrations were determined with GC-MS. In 8 out of these 15 patients the pharmacokinetics of intravenous midazolam was also studied.


RESULTS
Apparent oral clearance, apparent volume of distribution, plasma half-life and 1-OH-Midazolam/Midazolam AUC ratio were [median (range)]: 2.7 [0.67-15.5] ml kg(-1) min(-1), 1.4 [0.3-12.1] l kg(-1), 7.6 [1.2-15.1], h and 0.03 [0.01-0.96], respectively. Absolute bioavailability was 0.49 [0.12-1.0].


CONCLUSIONS
Midazolam oral clearance is markedly decreased in preterm infants as compared with older children, probably because of immature CYP3A4 activity.
de Wildt
S N
SN
Department of Paediatrics, Erasmus Medical Center Rotterdam, The Netherlands. dewildt@alkg.azr.nl
Kearns
G L
GL
Hop
W C J
WC
Murry
D J
DJ
Abdel-Rahman
S M
SM
van den Anker
J N
JN
D000284:Administration, Oral; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics*; D008658:Inactivation, Metabolic; D007231:Infant, Newborn; D007234:Infant, Premature / Q000378:metabolism*; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism
D006993:Hypnotics and Sedatives; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam