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Vol. 28, Issue 4, 379-382, April 2000
Depts. of Pharmaceutical Drug clearance is often higher in children than in adults,
particularly when normalized to body weight. We previously showed that
liver volume normalized to body weight was inversely related to age,
but that the systemic clearance of a nonspecific cytochrome P450
(CYP) substrate (antipyrine) was higher in young children compared with adults even when normalized per liver volume. Our purpose
herein was to evaluate whether P450 catalytic activities, expressed as
maximal catalytic rates per milligram of microsomal protein, differed
in up to 37 normal livers from subjects <10 (range 0.5-9 years of
age), >10 but <60 years of age (range 10-59 years), and >60 year
(range 63-93 years of age). There were no age-related differences in
the oxidation of ethoxyresorufin (P = .83)
(CYP1A2), ethoxycoumarin (P = .52) (CYP2E1 and
other P450s), teniposide (P = .58), midazolam
(P = .47) (CYP3A4/3A5), or paclitaxel (P = .24) (at the 17
Sciences (J.G.B., W.E.E., M.V.R.)
and Biostatistics and Epidemiology
(P.L.H.), St. Jude
Children's
Research Hospital; and University
of Tennessee
(W.E.E., M.V.R.),
Memphis, Tennessee
position, CYP2C8).
Tolbutamide hydroxylation tended to be lower in children versus adults
(P = .047) (CYP2C9), but did not reach statistical
significance after correcting for multiple comparisons. No relationship
was found to exist between age and microsomal recovery
(P = .98); thus, recovery did not account for the
lack of age-related differences in catalytic activity. We conclude that
increased intrinsic cytochrome P450 activity is unlikely to account for
increased clearance of most P450 drug substrates in children.
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