Abstract
We investigated the effect of antiemetic, antipsychotic, and Ca2+ blocker drugs on the function of P-glycoprotein (Pgp) in vitro and compared inhibitory concentrations with therapeutic blood levels. Human colon adenocarcinoma (Caco-2) and human blood-brain barrier endothelial cells were transfected or transduced to express Pgp, and the uptake of rhodamine123, calcein AM, or daunorubicin was measured by flow cytometry in the presence of the drugs. NIH3T3/MDR1 cells were used for reference testing. Results of the flow cytometric studies were supported by cell proliferation and monolayer permeability studies. Thirty-five drugs are included in this study, of which 13 modulate the function of Pgp at the therapeutic blood concentration and 8 at a concentration 2 to 4 times higher. Two drugs, which block the function of Pgp only partially at therapeutic blood concentrations, blocked the function of Pgp completely if used concomitantly. Based on these in vitro experiments, we conclude that administration of several drugs that modulate the function of Pgp simultaneously may adversely affect the natural function of this efflux pump and may cause drug-induced side effects in patients.
Footnotes
-
Send reprint requests to: Safaa Ibrahim, Ph.D., FDA/CDER, HFD-860, 5600 Fishers Ln., Rockville, MD 20857. E-mail:ibrahims{at}cder.fda.gov
- Abbreviations:
- Pgp
- P-glycoprotein
- mAb
- monoclonal antibody
- BBB
- blood-brain barrier
- RPMI
- Roswell Park Memorial Institute medium
- DN
- daunorubicin
- FI
- fluorescence intensity
- R123
- rhodamine123
- Received June 13, 2000.
- Accepted August 23, 2000.
- U.S. Government
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
