Drug Metabolism in the Neonate

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J. Ara b Neonatal Forum 2005; 2: 1-4
Drug Metabolism
in the Neonate
Imti Choonara
Academic Division of Child Health, University of Nottingham, Clinical Sciences Wing The Medical School, Derbyshire Children ’s Hospital, UK
_____________________________________________________________________________________________ Abstract
The newborn infant has a reduced capacity for drug metab olism in comp arison with infants and children. This is more marked in the preterm neonate. Altered drug metabolism may predispose the neonate to a greater risk of drug toxicity. Neonates usually require smaller doses of drugs administered less frequently than infants and children. Keywords: Drug metabolism – neonate – caffeine – midazolam – morphine – paracetamol The importance of drug metabolism in the neonate is

Different developmental patterns have been identified
illustrated by the chloramphenicol tragedy.
for CYPs involving activity in the fetal liver
1
Newborn infants who received chloramphenicol
(CYP3A7), minimal activity in the fetal liver but with
developed the grey baby syndrome. This involved
rapid increase hours after birth (CYP2D6 and
cardiovascular collapse, irregular respiration and
CYP2E1) and development in infancy (CYP1A2).
3– 6
subsequent death. Recognition that the newborn
For many drugs weight corrected clearance values are
infant was unable to metabolise chloramphenicol as
often low at birth but then increase rapidly reaching a
effectively as adults resulted in a reduction in the
maximum by 2 years of age.
total daily dosage from 100 mg/kg to 50 mg/kg. Use
of the lower dosage did not result in development of
CYP3A4
the grey baby syndrome.
The CYP3A subfamily is the most abundantly
expressed CYP subfamily in the human adult and
The biological purpose of drug metabolism is to
newborn liver. Moreover, this subfamily is involved
conv ert lipophilic (fat soluble) comp ounds into more
in the metabolism of more than h alf of all drugs,
polar and thus more water soluble substances that are
including cisapride, midazolam, fentanyl, lidocaine,
more readily excreted into bile or urine. The major
nifedipine, indinavir and verapamil.
7
site of drug metabolism is within the liv er. The
gastrointestinal tract, blood cells and other organs are
The CYP3A subfamily in humans consists of at least
also involved in drug metabolism. The enzymes
4 enzymes: CYP3A4, CYP3A5, CYP3A7 and
involved in drug metabolism are not only involved in
CYP3A43. CYP3A4 and CYP3A5 account for 30-
the breakdown of medicines but also the numerous
40% of total CYP con tent in the adult liver and
other chemicals that humans in gest or inhale either
intestine. CYP3A4 and CYP3A5 are differentially
deliberately or unwittingly.
expressed, but have largely overlapping substrate
specificity. CYP3A7 is the main CYP isoform in the
The major pathways involv ed in drug metabolism are
human fetal and newborn liver. From the few studies
divided into phase 1 and phase 2 reactions. Phase 1
available, it appears that the substrate specificity of
involves oxidation, reduction, hydrolysis and
CYP3A7 is different from CYP3A4.
hydration reactions. The major pathway is oxidation
which involves the cytochrome P450 dependent
In vitro
studies have shown that CYP3A7 activity is
(CYP) enzymes. The major CYP enzymes are
high directly after birth, while CYP3A4 activity is
CYP1A2, CYP2B6, CYP2C8 – 10, CYP2C19 ,
very low.
During the first days after birth a
3
CYP2D6, CYP2E1 and CYP3A4 and 5. The major
transition occurs from main ly CYP3A7 activity to
pathways for phase 2 involve glucuronidation,
CYP3A4 activity. Adult levels of CYP3A4 activity
sulphation, methylation, acetylation and glutathione
are reached during the first years of life. The lower
conjugation. Total cytochrome P450 content in the
enzyme activity is illustrated by the example of
fetal liver is between 30% and 60% of adult v alues...
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