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Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine
W R Crom1, M V Relling, M L Christensen
1Pharmacokinetics and Pharmacodynamics Section, St. Jude Children's Research Hospital, Memphis, TN 38105.
Insights
Pediatric drug metabolism differs between children and adults. Children exhibit higher antipyrine clearance but similar lorazepam clearance, indicating age-related variations in hepatic drug disposition.
Area of Science:
- Pharmacokinetics
- Pediatric Pharmacology
- Drug Metabolism
Background:
- Hepatic drug metabolism and conjugation are crucial for drug clearance.
- Understanding age-related differences in drug disposition is vital for optimizing pediatric therapeutics.
- Children with acute lymphocytic leukemia (ALL) may experience altered drug metabolism.
Purpose of the Study:
- To compare the disposition of antipyrine and lorazepam in children with ALL and healthy adults.
- To investigate age-specific differences in hepatic oxidative metabolism and conjugation pathways.
- To assess how body weight and body surface area normalization affects clearance parameters.
Main Methods:
- Administered intravenous antipyrine and lorazepam as model drug substrates.
- Evaluated drug disposition in 50 children with ALL in remission and 10 healthy adults.
- Normalized clearance values to body weight and body surface area for comparative analysis.
Main Results:
- Antipyrine clearance normalized to body weight was significantly higher in children (0.91 ml/min/kg) versus adults (0.59 ml/min/kg).
- Lorazepam total clearance (CL) and unbound clearance (CLu) normalized to body surface area were lower in children (CL=31.9 ml/min/m2, CLu=352 ml/min/m2) versus adults (CL=40.6 ml/min/m2, CLu=485 ml/min/m2).
- The fraction of unbound lorazepam was similar between pediatric and adult groups.
Conclusions:
- Significant age-related differences exist in the disposition of antipyrine and lorazepam.
- Children demonstrate higher antipyrine clearance per kilogram, suggesting enhanced oxidative metabolism.
- Lorazepam disposition shows differences when normalized to body surface area, highlighting complex pediatric pharmacokinetic profiles.
Abstract:
The disposition of intravenous antipyrine and lorazepam, administered as model substrates for hepatic oxidative metabolism and conjugation, was evaluated in 50 children (mean age, 7.8 years; range, 2.3 to 17.8 years) with acute lymphocytic leukemia in complete remission and compared with a group of ten healthy adults. Antipyrine clearance normalized to body weight was significantly greater in children than in adults (0.91 versus 0.59 ml/min/kg; p = 0.012), but was not different when normalized to body surface area. In contrast, lorazepam total clearance (CL) and unbound clearance (CLu) normalized to body weight were not significantly different between children and adults but were smaller in children when normalized to body surface area (CL = 31.9 versus 40.6 ml/min/m2, p = 0.036; CLu = 352 versus 485 ml/min/m2, p = 0.010). The mean lorazepam fraction unbound in children was 0.087, which was not different from adult volunteers (0.084). This study has identified significant differences between children and adults in the disposition of these two compounds, with higher milliliter per minute per kilogram clearance for antipyrine but not lorazepam.