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Vol. 303, Issue 1, 323-332, October 2002
Department of Pharmaceutical Sciences, St. Jude Children's
Research Hospital, Memphis, Tennessee (K.Y., L.L, J.D.S., E.G.S.);
Institut de Microbiologie, Centre Hospitalier UniversitaireVaudois,
Lausanne, Switzerland (D.S.); and Department of Pediatrics and the
Research Institute, The Hospital for Sick Children, Toronto, Ontario,
Canada (K.F.)
Many clinically important drug interactions occur due to inhibition of
human liver cytochrome P450 3A (CYP3A) metabolism. The drug efflux pump
P-glycoprotein (Pgp) can be an additional locus contributing to these
drug interactions because there is overlap in drugs that are substrates
for both proteins. We screened a number of CYP3A inhibitors (macrolide
antibiotics, azole antifungals, and ergotpeptides) for their ability to
interact with Pgp, compared with prototypical Pgp inhibitors. We used
cell lines expressing human, mouse, and rat mdr1 genes. Pgp antagonism
was defined by interactions of the drugs with four cell lines (LLC-PK1,
L-MDR1, L-mdr1a, and L-mdr1b) using a microfluorometric calcein-AM
assay and characterized for their inhibitor constant
(Ki) toward calcein-AM. The compounds were
further defined for their ability to inhibit MDR1 by their effect on
vinblastine accumulation into L-MDR1 cells. Representative compounds
from each class of drugs were further tested as Pgp substrates, defined
by the ability of human Pgp or mouse mdr1a/Pgp to transport them across
a polarized kidney epithelial cell in vitro. These same compounds were
administered radiolabeled in vivo to mdr1a (+/+) and (
/) mice and
the distribution of radioactivity compared. The results are summarized
as follows: 1) Some drug interactions with Pgp were substrate- and/or
assay-dependent. 2) Ergot alkaloids were identified as a class of
MDR1/Pgp chemosensitizers. 3) The Ergot alkaloids revealed species
differences in the structure-activity relationships for inhibition of
Pgp. Simultaneous inhibition of Pgp by many CYP3A inhibitors
contributes to human variation in the extent of drug-drug interactions.
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