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Vol. 58, Issue 4, 863-869, October 2000
Department of Pharmaceutical Sciences, St. Jude Children's
Research Hospital, Memphis, Tennessee (L.-B.L., E.G.S.); and Department
of Pharmaceutical Sciences, University of Tennessee, Memphis, Tennessee
(J.T.D.)
We determined whether the drug efflux protein P-glycoprotein (Pgp)
could influence the extent of CYP3A-mediated metabolism of
erythromycin, a widely used model substrate for CYP3A. We compared CYP3A metabolism of erythromycin (a Pgp substrate) using the
erythromycin breath test in mice proficient and deficient of
mdr1 drug transporters. We first injected
mdr1(+/+) mice with
[14C]N-methyl erythromycin and measured
the rate of appearance of 14CO2 in the breath
as a measure of hepatic CYP3A activity. Animals treated with CYP3A
inducers or inhibitor showed accelerated or diminished
14CO2 in the breath, respectively. The
erythromycin breath test was next administered to
mdr1a(
/) and mdr1a/1b(+/+) and
(/) mice. These animals had equivalent levels of immunoreactive
CYP3A and CYP3A activity as measured by erythromycin
N-demethylase activity in liver microsomes.
Nevertheless, the rate of 14CO2 appearance in
the breath showed no relationship with these measurements of CYP3A, but
changed proportionally to expression of mdr1. The average breath test
14CO2 area under the curves were 1.9- and
1.5-fold greater in mdr1a/1b(/) and
mdr1a(/) mice, respectively, compared with (+/+)
mice, and CERmax was 2-fold greater in
mdr1a/1b(/) compared with (+/+) mice. We conclude
that Pgp, by limiting intracellular substrate availability can be an
important determinant of CYP3A metabolism of numerous medications that
are substrates for CYP3A and Pgp.
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