Efflux of rhodamine from CD56+ cells as a surrogate marker for reversal of P-glycoprotein-mediated drug efflux by PSC 833

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

SN - 0006-4971

VL - 93

SP - 306

EP - 314

JO - Blood

JF - Blood

IS - 1

ER -