Due to organ immaturity, neonates have reduced hepatic metabolism and renal excretion. They also have very little cytochrome P450 enzyme activity. The concentration of cytochrome P450 in the newborn liver is only about 28% of adult levels. This has a protective component for the infant; if infants had adult levels of CYP enzymes, polar compounds formed from their reactions would accumulate in the fetus because of the fetoplacental barrier.
Neonates also have very low concentrations of UDP-glucuronyl transferase. This is evidenced by the high occurrence of jaundice in newborns. Recall that bilirubin is conjugated with UDP-glucuronyl transferase. Because of low concentrations of UDP-glucuronyl transferase, conversion to glucuronide is slower, resulting in potentially dangerous accumulations of metabolites or un-metabolized parent drugs.
Sulfate conjugation is well developed in newborns to nearly the same levels as in adults. The glutathione system is more active in neonates than in adults. It is for this reason that paracetamol (acetaminophen/Tylenol®) is not as toxic in neonates and young children as it is in adults. Paracetamol is predominately metabolized to inactive glucuronide and sulfate conjugates secreted in the urine. CYP3A4 and CYP2E1 metabolize a small amount of the drug to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is almost immediately detoxified by glutathione conjugation in the liver. However, in the case of overdose, the conjugation with glucuronide and sulfate becomes overwhelming, to the extent that glutathione has to compensate by taking on the full brunt of metabolizing the drug. When the glutathione stores are depleted, unconjugated NAPQI accumulates. NAPQI, in its unconjugated state, is free to bind to proteins and subcellular structures, causing rapid necrosis of liver cells and possible liver failure. Because glutathione conjugation is more active in neonates, the toxic NAPQI does not accumulate nearly as rapidly.
