Inhibitory effect of human immunodeficiency virus protease inhibitors on multidrug resistance transporter P-glycoproteins

The objective of this study was to determine whether human immunodeficiency virus (HIV) protease inhibitors (saquinavir, ritonavir and nelfinavir) int eract with other HIV protease inhibitors and/or HIV reverse transcriptase i nhibitors (zidovudine, didanosine, lamivudine, zalcitabine and sanilvudine) . We measured transport of nelfinavir, an HIV protease inhibitor which is k nown as a substrate for the multidrug resistance transporter P-glycoprotein (P-gp), in an epithelial monolayer model and K-i for P-gp of some drugs by a calcein flux assay. Transport in a basal to apical direction was 2-fold g reater than apical to basal flux for nelfinavir, K-i for P-gp of a potent P -gp inhibitor cyclosporin A was 1.09 muM and those of ritonavir and nelfina vir were 111 muM and 28.6 muM, whereas all HIV reverse transcriptase inhibi tors gave high K-i values. These data show that nelfinavir, which is a subs trate for P-gp, inhibits a P-gp function as a drug efflux pump and that HIV reverse transcriptase inhibitors do not inhibit P-gp.