Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions

2007 ◽  
Vol 35 (10) ◽  
pp. 1853-1859 ◽  
Author(s):  
Vaishali Dixit ◽  
Niresh Hariparsad ◽  
Fang Li ◽  
Pankaj Desai ◽  
Kenneth E. Thummel ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cytochrome P450 ◽  
Drug Interactions ◽  
Protease Inhibitors ◽  
Human Hepatocytes ◽  
Cytochrome P450 Enzymes ◽  
Human Immunodeficiency Virus Protease ◽  
Immunodeficiency Virus ◽  
Clinical Drug

scholarly journals Effects of Human Immunodeficiency Virus Protease Inhibitors on the Intestinal Absorption of Tenofovir Disoproxil Fumarate In Vitro

2007 ◽  
Vol 51 (10) ◽  
pp. 3498-3504 ◽  
Author(s):  
Leah Tong ◽  
Truc K. Phan ◽  
Kelly L. Robinson ◽  
Darius Babusis ◽  
Robert Strab ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Interactions ◽  
Intestinal Absorption ◽  
Protease Inhibitors ◽  
Plasma Levels ◽  
Human Immunodeficiency Virus Protease ◽  
Mdckii Cells ◽  
Immunodeficiency Virus ◽  
Secretory Transport

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 μM (lopinavir) to >100 μM (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.

scholarly journals Multiple Mutations in the Human Immunodeficiency Virus Protease Gene Are Responsible for Decreased Susceptibility to Protease Inhibitors

1995 ◽  
Vol 6 (2) ◽  
pp. 80-88 ◽  
Author(s):  
R. W. King ◽  
S. Garber ◽  
D. L. Winslow ◽  
C. Reid ◽  
L. T. Bacheler ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Clinical Isolate ◽  
Protease Gene ◽  
Human Immunodeficiency Virus Protease ◽  
Fold Reduction ◽  
Antiretroviral Drug ◽  
Immunodeficiency Virus ◽  
Hiv 1

The protease (PR) of the human immunodeficiency virus (HIV) is essential for replication of the virus, and accordingly has become an attractive target for the development of an antiretroviral drug. We have previously reported that passage of HIV-1 in the presence of increasing concentrations of the C-2 symmetrical, linear diol P9941 resulted in the isolation of virus with a valine-to-alanine change at position 82 (V82A) of the PR, and reduced sensitivity to certain PR inhibitors. In this study, we passaged four different variants of HIV-1 in increasing concentrations of XM323, and isolated variants with reduced sensitivity to inhibitors of PR. Twenty-three passages of HIV-1 (RF) in the presence of XM323 resulted in a variant that exhibited an approximately 100-fold reduction in susceptibility to XM323 and that contained V82F and I84V changes. When two other viruses, HIV-1 (RF41D2) and HIV-1(RF41E4), previously derived from HIV-1 (RF) by passage in the presence of P9941, were passaged in the presence of XM323, variants with V82A/L97V and M46L/V82A/L97V changes, respectively, were obtained. The M46L/V82A/L97V variant showed a 6-fold reduction in sensitivity to XM323, whereas the susceptibility of the V82A/L97V mutant remained unchanged. Seventeen passages of a clinical isolate of HIV-1, HIV-1 (Pat.E), in the presence of XM323 produced a V82F/L97V mutant with an approximately 9-fold reduction in sensitivity to XM323.

Water-Soluble Prodrugs of the Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir

2009 ◽  
Vol 52 (9) ◽  
pp. 2964-2970 ◽  
Author(s):  
David A. DeGoey ◽  
David J. Grampovnik ◽  
William J. Flosi ◽  
Kennan C. Marsh ◽  
Xiu C. Wang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Water Soluble ◽  
Human Immunodeficiency Virus Protease ◽  
Immunodeficiency Virus
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