HIV protease inhibitors are essential components of most recommended treatment regimens for
HIV infection. They are always coadministered with
ritonavir as a pharmacokinetic booster. Their bioavailability may be impaired because they are substrates of
CYP3A4 and several transporters, including
P-glycoprotein. The aim of this study was to explore the impact of
ritonavir on the intestinal absorption of
HIV protease inhibitors in two models: the Caco-2 system and the in situ intestinal perfusion model with mesenteric blood sampling in mice. Using the Caco-2 system, the effect of
ritonavir on the permeability of the other
HIV protease inhibitors was significant for
saquinavir (2-fold increase) and
indinavir (3-fold increase), negligible for
darunavir and
amprenavir, and nonexistent for
nelfinavir,
lopinavir,
tipranavir, and
atazanavir. However, performing the in situ intestinal perfusion technique in mice for three selected
HIV protease inhibitors showed a significant increase in the intestinal permeability for all:
indinavir (3.2-fold),
lopinavir (2.3-fold), and
darunavir (3-fold). The effect of aminobenzotriazole (a nonspecific
cytochrome P450 inhibitor) on
lopinavir permeability was comparable with using
ritonavir, whereas there was no effect for
indinavir and
darunavir. We conclude that
ritonavir can boost
drug absorption by inhibiting
P-glycoprotein and/or metabolism, in a compound-specific manner. The results of this study illustrate that a combination of absorption models needs to be considered to elucidate
drug-drug interactions at the level of the intestinal mucosa.