pediatrics
Pharmacokinetics in Children
Metabolism and elimination
Drug metabolism and elimination vary with age and depend on the substrate or drug, but most drugs, and most notablyphenytoin, barbiturates, analgesics, and cardiac glycosides, have plasma half-lives 2 to 3 times longer in neonates than in adults. The cytochrome P-450 (CYP450) enzyme system in the small bowel and liver is the most important known system for drug metabolism. CYP450 enzymes inactivate drugs via Oxidation, reduction, and hydrolysis (phase I metabolism) Hydroxylation and conjugation (phase II metabolism) ) 2 to 4 weeks postnatally. CYP450 activity can also be induced (reducing drug concentrations and effect) or inhibited (augmenting concentrations and effect) by coadministered drugs. These drug interactions may lead to drug toxicity when CYP450 activity is inhibited or to an inadequate drug level when CYP450 activity is induced. Diet may also affect development of CYP450 activity in children ( Metabolism and elimination reference ). Kidneys, lungs, and skin also play a role in the metabolism of some drugs, as do intestinal drug-metabolizing enzymes in neonates. Phase II metabolismvaries considerably by substrate. Maturation of enzymes responsible for bilirubin andacetaminophenconjugation is delayed; enzymes responsible formorphineconjugation are fully mature even in preterm infants. Drug metabolites are eliminated primarily through bile or the kidneys. Renal elimination depends on Plasma protein binding Renal blood flow Glomerular filtration rate Tubular secretion All of these factors are altered in the first 2 years of life. Renal plasma flow is low at birth (12 mL/minute) and reaches adult levels of 140 mL/minute by age 1 year. Similarly, glomerular filtration rate is 2 to 4 mL/minute at birth, increases to 8 to 20 mL/minute by 2 to 3 days, and reaches adult levels of 120 mL/minute by 3 to 5 months. 