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.