Related Experiment Videos
The P-glycoprotein-mediated relative decrease in cytosolic free drug concentration is similar for several
H S Mülder1, H Dekker, H M Pinedo
1University Hospital Vrije Universiteit, Department of Medical Oncology, Amsterdam, The Netherlands.
Biochemical Pharmacology
|September 28, 1995
Summary
P-glycoprotein (P-gp) activity similarly reduces cytosolic drug levels for various anthracyclines. Increased lipophilicity enhances drug permeation and P-gp pumping, affecting cytotoxicity in multidrug-resistant cells.
Area of Science:
- Pharmacology
- Cell Biology
- Biochemistry
Background:
- P-glycoprotein (P-gp) is a key mediator of multidrug resistance (MDR) in cancer cells.
- P-gp activity lowers intracellular drug concentrations, reducing the efficacy of chemotherapeutic agents like anthracyclines.
- Lipophilicity of anthracyclines influences their interaction with P-gp and clinical outcomes, as seen with idarubicin (IDA) in acute myeloid leukemias (AML).
Purpose of the Study:
- To investigate how variations in passive drug influx and P-gp-mediated efflux affect cytosolic drug concentrations and cytotoxicity for a series of anthracyclines.
- To correlate drug lipophilicity with P-gp activity, drug permeation, and cellular drug accumulation.
- To understand the mechanisms underlying differential efficacy of anthracyclines in P-gp-expressing MDR cells.
Main Methods:
- Utilized a novel flow-through system to measure passive permeation, P-gp pumping rates, and cytosolic drug concentrations in MDR KB8-5 cells.
- Tested six anthracyclines (doxorubicin, daunorubicin, epidoxorubicin, IDA, cyano-morpholino-doxorubicin, carminomycin) ordered by lipophilicity.
- Assessed drug cytotoxicity (IC50 values) and resistance factors, and evaluated the effect of verapamil on reversing resistance.
Main Results:
- Both passive drug permeation and P-gp pumping rates increased with anthracycline lipophilicity.
- P-gp reduced cytosolic free drug concentrations by a similar extent (40-50%) for all tested anthracyclines.
- Anthracyclines with higher lipophilicity (CMD, IDA, CAR) exhibited lower IC50 values and resistance factors compared to less lipophilic ones (DOX, DNR, EPI).
- Verapamil effectively reversed P-gp-mediated resistance across all tested anthracyclines.
Conclusions:
- P-gp activity causes a comparable relative decrease in intracellular drug levels for various anthracyclines, irrespective of their lipophilicity.
- The lower resistance factor observed for IDA compared to DNR is not attributable to P-gp's inability to export IDA.
- Drug lipophilicity influences both cellular uptake and P-gp efflux, impacting overall cytotoxicity in MDR cancer cells.