Drug metabolism and clearance in neonates children and elderly

In the fetus, CYP3A7 is the major hepatic cytochrome responsible for steroid metabolism. Variably expressed in the fetus, CYP3A5 is also present in significant level in half of the children. However, in adults, CYP3A4 is the major functional hepatic enzyme responsible for metabolism of many drugs. CYP1A1 is also present during organogenesis whereas CYP2E1 may be present in some second trimester fetuses. After birth, hepatic CYP2D6, CYP2C8/9, and CYP2C18/19 are activated. CYP1A2 becomes active during the fourth to fifth months after birth (100).

In general, age is not considered to have a major influence on the absorption of drugs from the gut except for the first few weeks of life when absorption steps may be less efficient. Neonates and infants demonstrate increased total body water to body fat ratio compared with adults whereas the reverse is observed in the elderly. These factors may affect Vd of drugs depending on their lipophilic character in infants and elderly compared with that in adult population. Moreover, altered plasma binding of drugs may be observed in both neonates and some elderly because of low albumin, thus increasing the fraction of free drug. Moreover, drug-metabolizing capacity by the liver enzymes is reduced in newborns particularly in premature babies but increases rapidly during the first few weeks and months of life to reach values which are generally higher than adult-metabolizing rates. In contrast, efficiency of cytochrome P450 enzymes declines with old age. Renal function at the time of birth is reduced by more than 50% of adult value but then increases rapidly in the first 2-3 years of life. Renal function then starts declining with old age. Oral clearance of lamotrigine, topiramate, levetiracetam, oxcar-bazepine, gabapentin, tiagabine, zonisamide, vigabatrin, and felbamate is significantly higher (20-120%) in children compared with that in adults depending on the drug and the age distribution of the population. On the contrary, clearance of these drugs is reduced (10-50%) in the elderly population compared with that in the middle-aged adults (101).

Clearance of aminoglycoside is dependent on the GFR, which is markedly decreased in neonates, especially in premature newborns. These drugs appear to be less nephro-toxic and ototoxic in neonates compared with that in the adult population. The Vd of aminoglycoside increases in neonates, which may also contribute to a longer half-life of aminoglycoside in neonates. Decreased renal clearance in neonates is responsible for decreased clearance of most beta-lactam antibiotics (102). Higher Vd and lower clearance of gentamicin was also observed in neonates (103). Conversion of theophylline to caffeine in human fetuses has been reported (104). Kraus et al. studied maturational changes in theophylline disposition in 52 infants and observed

Table 3

Factors and Diseases Affecting Disposition of Drugs

Factor or disease

Comments

Gender difference

Alcohol intake

Smoking

Hepatic impairment Renal impairment

Thyroid disease Cardiovascular disease Pregnancy

Children

Men may have faster clearance of drugs than women except for drugs cleared by CYP3A4 Women may be more susceptible to drug toxicity

Pharmacodynamic interactions with many drugs causing significant toxicity with lower amounts of drugs when alcohol is present Cimetidine and ranitidine may increase blood alcohol level Alcohol may increase International Normalization Ratio

(INR) in patients taking warfarin Alcohol increases serum levels of amitriptyline

Theophylline serum concentrations reduced in smokers Reduced serum concentrations of many other drugs

Interaction with warfarin Decreased clearance of tacrolimus and sirolimus requiring dosage reduction Elevated free concentrations of strongly protein-bound drugs

Decreased clearance of drugs where renal excretion is the major pathway Elevated free concentrations of strongly protein-bound drugs

Elevated concentration of certain drugs (cyclosporine, phenobarbital etc.) in hypothyroidism Thyrotoxicosis may reduce warfarin requirement Reduced metabolism of many drugs because of decreases in hepatic blood flow. Reduced clearance of digoxin, theophylline, and other drugs

Elevated free concentrations of drugs because of reduced plasma proteins Increased metabolism of certain drugs (phenytoin, indinavir), but clearance of some drugs (theophylline) may also be reduced Lower serum concentration of lithium

Increase oral clearances of many antiepileptic drugs Conversion of theophylline to caffeine in children that postconceptional age was an import factor in describing theophylline metabolism in neonates. Disappearance of serum caffeine concentrations and maturation of theophylline clearance were primarily related to the demethylation pathway that produced 3-methylxanthine. Theophylline clearance and urine metabolite pattern reached adult values in infants 55 weeks after postconceptional age (105). Major factors affecting drug distribution and metabolism are summarized in Table 3.

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