Efflux of rhodamine from CD56+ cells as a surrogate marker for reversal of P-glycoprotein-mediated drug efflux by PSC 833
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Efflux of rhodamine from CD56+ cells as a surrogate marker for reversal of P-glycoprotein-mediated drug efflux by PSC 833. / Robey, R; Bakke, S; Stein, W; Meadows, B; Litman, Thomas; Patil, S; Smith, T; Fojo, T; Bates, S.
In: Blood, Vol. 93, No. 1, 01.01.1999, p. 306-14.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Efflux of rhodamine from CD56+ cells as a surrogate marker for reversal of P-glycoprotein-mediated drug efflux by PSC 833
AU - Robey, R
AU - Bakke, S
AU - Stein, W
AU - Meadows, B
AU - Litman, Thomas
AU - Patil, S
AU - Smith, T
AU - Fojo, T
AU - Bates, S
PY - 1999/1/1
Y1 - 1999/1/1
N2 - 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.
AB - 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.
KW - Administration, Oral
KW - Adult
KW - Aged
KW - Antigens, CD56
KW - Antineoplastic Agents
KW - Biological Markers
KW - Biological Transport
KW - Cells, Cultured
KW - Cyclosporins
KW - Drug Resistance, Multiple
KW - Humans
KW - Leukocytes, Mononuclear
KW - Middle Aged
KW - P-Glycoprotein
KW - Paclitaxel
KW - Rhodamines
KW - Staining and Labeling
KW - Tumor Cells, Cultured
KW - Vinblastine
M3 - Journal article
C2 - 9864175
VL - 93
SP - 306
EP - 314
JO - Blood
JF - Blood
SN - 0006-4971
IS - 1
ER -
ID: 119647741