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1. Drug Metab Dispos. 2012 May 1. [Epub ahead of print]

Boosting of HIV Protease Inhibitors by Ritonavir in the Intestine: The Relative
Role of Cyp and P-gp Inhibition Based on Caco-2 monolayers Versus In Situ
Intestinal Perfusion in Mice.

Holmstock NF, Annaert PP, Augustijns P.

Katholieke Universiteit Leuven.

HIV protease inhibitors are essential components of most recommended treatment
regimens for HIV infection. They are always co-administered with ritonavir as a
pharmacokinetic booster. Their bioavailability may be impaired due to the fact
that 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 non-existent for nelfinavir, lopinavir, tipranavir and
atazanavir. However, performing the in situ intestinal perfusion technique in
mice for 3 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 Cyp
inhibitor) on lopinavir permeability was comparable to using ritonavir, while
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.

PMID: 22550269 [PubMed - as supplied by publisher]