Boosting of HIV Protease Inhibitors by Ritonavir in the Intestine: The Relative Role of Cytochrome P450 and P-Glycoprotein Inhibition Based on Caco-2 Monolayers versus In Situ Intestinal Perfusion in Mice

Abstract

ABSTRACT: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.

Improving intestinal absorption and oral bioavailability of curcumin via taurocholic acid-modified nanostructured lipid carriers

“…44 Here, this method was used to observe the absorption performances of Cur solution and different Cur-loaded NLCs in different rat intestinal segments, because it allows experimentation in the actual intestinal environment. 45 As shown in Figure 4A and B, Cur solution had maximal K a and P eff values in the duodenum among the three intestinal segments. Intestinal absorption was obviously enhanced by loading Cur into NLCs, since K a and P eff values were significantly elevated in Cur NLCs in comparison to Cur solution in every corresponding intestinal section.…”

Assessment of absorption of four lignan constituents of JingNing particles in rat gut using <i>in situ</i> single-pass intestinal perfusion

“…These include in vivo, in vitro and in situ methods [10][11][12]. In situ methods have many advantages in that they provide viable intestinal mucosa, nerve system and blood flow, as well as the expression of specific enzymes and transporters [ 13]. Single-pass intestinal perfusion is widely used for studying intestinal absorption of drugs due to its high degree of accuracy [14][15][16][17].…”

Simultaneous Quantification of Novel Antiretroviral Drug Combination by Stability-indicating High Performance Liquid Chromatography Method

“…Few reports have described bioanalytical methods for simultaneous detection of lopinavir and ritonavir, alone or in combination with additional PI and NNRTI, from plasma and/or cell samples [3,[5][6][7][8][9] . Some methods detect tenofovir alone or in combination with other drugs, such as lamivudine [10][11][12] .…”