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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 306-314
Efflux of Rhodamine From CD56+ Cells as a Surrogate
Marker for Reversal of P-Glycoprotein-Mediated Drug Efflux by PSC 833
Robert Robey,
Susan Bakke,
Wilfred Stein,
Beverly Meadows,
Thomas Litman,
Sheela Patil,
Tom Smith,
Tito Fojo, and
Susan Bates
From the Medicine Branch, National Cancer Institute, National
Institutes of Health, Bethesda, MD; the Hebrew University of Jerusalem,
Jerusalem, Israel; and Novartis Pharmaceutical Corporation, East
Hanover, NJ.
The expression of high levels of P-glycoprotein (Pgp) in circulating
mononuclear cells allowed us to use an ex vivo assay as a surrogate
measure of Pgp antagonism. Efflux of rhodamine from CD56+
cells was measured before the start of PSC 833 and at varying times
thereafter. Patients receiving PSC 833 had decreased rhodamine efflux
from their circulating CD56+ cells. Time course studies
showed that following a single oral dose of PSC 833, decreased
rhodamine efflux was found in some patients within 15 minutes of
treatment. Maximal inhibition was observed at times ranging from 45 minutes to 60 minutes. A dose-response relationship was shown between
the concentration of PSC 833 in the blood and the inhibition of
rhodamine efflux, with an apparent plateau of the inhibition of
rhodamine efflux at approximately 1,000 ng/mL. The Ki,
defined as the concentration required for half-maximal inhibition of
Pgp-mediated rhodamine efflux, was determined to be in the range of 29 to 181 ng/mL; although results in two patients were distinctly
different, with Ki values of 914 and 916 ng/mL. MRK-16 staining was similar among all patients. We conclude that
measurement of rhodamine efflux from CD56+ cells
provides a surrogate assay with the potential for monitoring Pgp
antagonism in clinical trials.
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