The major pathways involved in
drug metabolism are divided into phase I (oxidation, reduction, hydrolysis, and
hydration) and phase II (glucuronida-tion, sulphation, methylation, and
acetylation) reactions. As a general rule, the clearance of drugs in the
neonatal period is reduced. For many drugs adult clearance values are reached
by the age of 2yrs.
The major pathway is oxidation
which involves the cytochrome P450 enzymes (CYP). The major CYP enzymes are
CYP3A4 and CYP1A2.
CYP3A4: this is responsible for the
metabolism of many drugs (e.g. midazolam,
ciclosporin, fentanyl, nifedipine). CYP3A4 activity is reduced in the neonatal
period and early infancy. Enzyme activity between individuals varies
considerably leading to a large range of plasma concentrations after the same dose
of an affected drug.
CYP1A2: accounts for 13% of total enzyme
activity in the liver. Caffeine and
theophylline are metabolized via the CYP1A2 pathway. Enzyme activity is reduced
in the neonatal period, but increases rapidly such that by the age of 6 months
activity approaches that of older children and adults.
Glucuronidation and sulphation are
the two major pathways. Glucuronidation is reduced in the neonatal period and
there is compensa-tory sulphation. The development of glucuronidation varies
for different drugs. For example, children who are 2yrs old have rates of
glucuronida-tion for morphine similar to those in adults, whilst for
paracetamol adult rates of glucuronidation are not reached until puberty.