Developmental changes in the liver weight- and body weight-normalized clearance of theophylline, phenytoin and cyclosporine in children.
OBJECTIVE
Body weight- (BW) normalized pediatric dosages of metabolically eliminated drugs often exceed the corresponding adult values. We aimed to clarify whether such findings would be attributable either to an augmented hepatic drug-metabolizing activity or to a systematic bias introduced by adopting BW as a size standard of clearance.


METHODS
We chose 3 model drugs that are metabolized by distinct cytochrome P450 (CYP) isoforms (theophylline, phenytoin and cyclosporine for CYPIA2, CYP2C9/2C19 and CYP3A4, respectively). The MEDLINE database covering 1966 to May 2001, was searched for articles where systemic clearance oftheophylline or oral clearance of cyclosporine and Vmax/ Km of phenytoin were reported with demographic data of individual children. Liver weights (LWs) of children were estimated using the equation constructed based upon the autopsy data in literature, and body surface area (BSA) was calculated using a standard formula. Relationships between age and clearance of the 3 model drugs that were normalized against BW, LW and BSA were examined. The analysis was confined to the data obtained from children older than 1 year due to scarcity of data for infants and neonates.


RESULTS
Relevant data were obtained from 24, 46 and 14 children for theophylline, phenytoin and cyclosporine, respectively. The development of LW lags behind that of BW but is almost identical to that of BSA. Thus, children had a greater LW/BW ratio than adults. The BW-normalized clearance of theophylline and Vmax/Km of phenytoin showed significantly (p < 0.01) negative correlations with age (r = -0.43 and -0.50, respectively) during childhood, whereas their LW- or BSA-normalized clearances were independent of age.


CONCLUSIONS
While our analyses were made upon limited numbers of subjects and range of age, the results suggest that children appear to have an augmented BW-normalized clearance for drugs of which metabolism is dominated by the CYP1A2, CYP2C9 or CYP3A4 due mainly to a lagged development of BW than that of LW during childhood. BSA would serve as a practical alternative to LW for scaling adult dosage of metabolically eliminated drugs to children.
Kanamori
M
M
Postgraduate School of Clinical Pharmacy, Meiji Pharmaceutical University, Tokyo, Japan.
Takahashi
H
H
Echizen
H
H
D000284:Administration, Oral; D000293:Adolescent; D000367:Age Factors; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001830:Body Surface Area; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000254:growth & development* / Q000378:metabolism* / Q000502:physiology; D008657:Metabolic Clearance Rate / Q000502:physiology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008954:Models, Biological; D009929:Organ Size; D010672:Phenytoin / Q000378:metabolism*; D013806:Theophylline / Q000378:metabolism*
D010672:Phenytoin; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human