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
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2012 |
|---|---|
| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:40 |
|---|---|
| Enthalten in: |
Drug metabolism and disposition: the biological fate of chemicals - 40(2012), 8 vom: 01. Aug., Seite 1473-7 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Holmstock, Nico [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
ATP Binding Cassette Transporter, Subfamily B, Member 1 |
|---|
| Anmerkungen: |
Date Completed 19.11.2012 Date Revised 31.03.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1124/dmd.112.044677 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM217450318 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM217450318 | ||
| 003 | DE-627 | ||
| 005 | 20231224034110.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2012 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1124/dmd.112.044677 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0725.xml |
| 035 | |a (DE-627)NLM217450318 | ||
| 035 | |a (NLM)22550269 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Holmstock, Nico |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Boosting of HIV protease inhibitors by ritonavir in the intestine |b the relative role of cytochrome P450 and P-glycoprotein inhibition based on Caco-2 monolayers versus in situ intestinal perfusion in mice |
| 264 | 1 | |c 2012 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 19.11.2012 | ||
| 500 | |a Date Revised 31.03.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a ATP Binding Cassette Transporter, Subfamily B, Member 1 |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a HIV Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Ritonavir |2 NLM | |
| 650 | 7 | |a O3J8G9O825 |2 NLM | |
| 700 | 1 | |a Annaert, Pieter |e verfasserin |4 aut | |
| 700 | 1 | |a Augustijns, Patrick |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Drug metabolism and disposition: the biological fate of chemicals |d 1990 |g 40(2012), 8 vom: 01. Aug., Seite 1473-7 |w (DE-627)NLM000015857 |x 1521-009X |7 nnns |
| 773 | 1 | 8 | |g volume:40 |g year:2012 |g number:8 |g day:01 |g month:08 |g pages:1473-7 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1124/dmd.112.044677 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 40 |j 2012 |e 8 |b 01 |c 08 |h 1473-7 | ||