Liver volume as a determinant of drug clearance in children and adolescents

Many drugs eliminated by the liver exhibit age-related differences in systemic clearance, necessitating different dosage requirements in children and adults. However, the physiological basis for these age-related changes is not well defined, including the importance of liver size in determining systemic clearance. Therefore, magnetic resonance imaging was used to determine liver volume in pediatric and adolescent patients, in whom systemic clearance of three model substrates [lorazepam (0.03 mg/kg), antipyrine (10 mg/kg), and indocyanine green (ICG; 0.5 mg/kg)] was also determined. In 16 children (ages 3.3-18.8 years; 8 boys), liver volume ranged from 469 to 1640 ml (median 973), and was significantly related to age, body weight, and body surface area (BSA). Younger children had larger livers normalized to body weight (ml/kg), but there was no difference when liver volume was normalized to BSA (ml/m²). Unnormalized lorazepam and ICG clearances (ml/min) were significantly related to absolute liver volume (r² = 50.2% and 31.4%, respectively), whereas unnormalized antipyrine clearance was not. Lorazepam, ICG, and antipyrine clearance normalized to BSA did not exhibit age-related changes, nor did lorazepam or ICG clearance normalized to body weight. However, antipyrine clearance normalized to body weight decreased significantly with increasing age (r² = 36.9%, p = 0.012), as did antipyrine clearance relative to liver volume. Thus, age-related changes in drug clearance and the importance of liver volume may differ based on the principal hepatic mechanisms involved in drug elimination.