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Human cytochrome P450 maximal activities in pediatric versus adult liver

J G Blanco1, P L Harrison, W E Evans

  • 1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|March 22, 2000
PubMed

Insights

Drug clearance is higher in children, but intrinsic cytochrome P450 (CYP) enzyme activity per liver protein does not explain this difference. This suggests other factors influence pediatric drug metabolism and clearance.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Pediatrics

Background:

  • Drug clearance is generally higher in children than adults, even when adjusted for body weight.
  • Previous studies indicated higher systemic clearance of a cytochrome P450 (CYP) substrate in young children compared to adults, even normalized per liver volume.

Purpose of the Study:

  • To investigate age-related differences in the intrinsic catalytic activities of major cytochrome P450 (CYP) enzymes in human liver microsomes.
  • To determine if differences in P450 enzyme activity contribute to the higher drug clearance observed in children.

Main Methods:

  • Assessed maximal catalytic rates (Vmax) of various CYP enzymes (CYP1A2, CYP2E1, CYP3A4/3A5, CYP2C8, CYP2C9) using specific substrates.
  • Analyzed liver samples from three age groups: <10 years, 10-59 years, and >60 years.
  • Correlated CYP catalytic activity with age and microsomal protein recovery.

Main Results:

  • No significant age-related differences were found in the catalytic activities of CYP1A2, CYP2E1, CYP3A4/3A5, or CYP2C8.
  • A trend towards lower tolbutamide hydroxylation (CYP2C9) in children was observed but did not reach statistical significance after correction.
  • Microsomal recovery showed no relationship with age, ruling it out as a confounding factor.

Conclusions:

  • Increased intrinsic cytochrome P450 activity is unlikely to be the primary reason for higher drug clearance of most P450 substrates in children.
  • The elevated drug clearance in pediatric populations likely results from factors other than intrinsic P450 enzyme capacity.

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