Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro.

Article Details

Citation

Tong L, Phan TK, Robinson KL, Babusis D, Strab R, Bhoopathy S, Hidalgo IJ, Rhodes GR, Ray AS

Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro.

Antimicrob Agents Chemother. 2007 Oct;51(10):3498-504. Epub 2007 Jul 30.

PubMed ID
17664327 [ View in PubMed
]
Abstract

Human immunodeficiency virus protease inhibitors (PIs) modestly affect the plasma pharmacokinetics of tenofovir (TFV; -15% to +37% change in exposure) following coadministration with the oral prodrug TFV disoproxil fumarate (TDF) by a previously undefined mechanism. TDF permeation was found to be reduced by the combined action of ester cleavage and efflux transport in vitro. Saturable TDF efflux observed in Caco-2 cells suggests that at pharmacologically relevant intestinal concentrations, transport has only a limited effect on TDF absorption, thus minimizing the magnitude of potential intestinal drug interactions. Most tested PIs increased apical-to-basolateral TDF permeation and decreased secretory transport in MDCKII cells overexpressing P-glycoprotein (Pgp; MDCKII-MDR1 cells) and Caco-2 cells. PIs were found to cause a multifactorial effect on the barriers to TDF absorption. All PIs showed similar levels of inhibition of esterase-dependent degradation of TDF in an intestinal subcellular fraction, except for amprenavir, which was found to be a weaker inhibitor. All PIs caused a dose-dependent increase in the accumulation of a model Pgp substrate in MDCKII-MDR1 cells. Pgp inhibition constants ranged from 10.3 microM (lopinavir) to >100 microM (amprenavir, indinavir, and darunavir). Analogous to hepatic cytochrome P450-mediated drug interactions, we propose that the relative differences in perturbations in TFV plasma levels when TDF is coadministered with PIs are based in part on the net effect of inhibition and induction of intestinal Pgp by PIs. Combined with prior studies, these findings indicate that intestinal absorption is the mechanism for changes in TFV plasma levels when TDF is coadministered with PIs.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AmprenavirP-glycoprotein 1IC 50 (nM)>100000N/AN/ADetails
AtazanavirP-glycoprotein 1IC 50 (nM)67800N/AN/ADetails
CyclosporineP-glycoprotein 1IC 50 (nM)9340N/AN/ADetails
IndinavirP-glycoprotein 1IC 50 (nM)>100000N/AN/ADetails
LopinavirP-glycoprotein 1IC 50 (nM)10300N/AN/ADetails
RitonavirP-glycoprotein 1IC 50 (nM)39600N/AN/ADetails
SaquinavirP-glycoprotein 1IC 50 (nM)100000N/AN/ADetails
Drug Interactions
DrugsInteraction
Darunavir
Tenofovir disoproxil
The serum concentration of Darunavir can be increased when it is combined with Tenofovir disoproxil.
Darunavir
Tenofovir
The serum concentration of Darunavir can be increased when it is combined with Tenofovir.
Tipranavir
Tenofovir disoproxil
The serum concentration of Tipranavir can be decreased when it is combined with Tenofovir disoproxil.
Tipranavir
Tenofovir alafenamide
The serum concentration of Tipranavir can be decreased when it is combined with Tenofovir alafenamide.
Tipranavir
Tenofovir
The serum concentration of Tipranavir can be decreased when it is combined with Tenofovir.
Interactions
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