INTERACTION OF ANTI-HIV PROTEASE INHIBITORS WITH THE MULTIDRUG TRANSPORTER P-GLYCOPROTEIN (P-GP) IN HUMAN CULTURED-CELLS

The anti-HIV protease inhibitors represent a new class of agents for t reatment of HIV infection. Saquinavir, ritonavir, indinavir, and nelfi navir are the first drugs approved in this class and significantly red uce HIV RNA copy number with minimal adverse effects. They are all sub strates of cytochrome P450 3A4, and are incompletely bioavailable. The drug transporting protein, P-glycoprotein (P-gp), which is highly exp ressed in the intestinal mucosa, could be responsible for the low oral bioavailability of these and other drugs which are substrates for thi s transporter. To determine whether these protease inhibitors are modu lators of P-gp, we studied them in cell lines which do and do not expr ess P-Xp. Saquinavir, ritonavir and nelfinavir significantly inhibited the efflux of [H-3]paclitaxel and [H-3]vinblastine in P-gp-positive c ells, resulting in an increase in intracellular accumulation of these drugs. However, similar concentrations of indinavir did not affect the accumulation of these anticancer agents. In photoaffinity labeling st udies, saquinavir and ritonavir displaced [H-3]a-zidopine, a substrate for P-gp, in a dose-dependent manner. These data suggest that saquina vir, ritonavir, and nelfinavir are inhibitors and possibly substrates of P-gp. Because saquinavir has a low bioavailability, its interaction with P-gp may be involved in limiting its absorption.