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1.
PLoS One ; 13(5): e0197474, 2018.
Article in English | MEDLINE | ID: mdl-29758082

ABSTRACT

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments.


Subject(s)
Antibodies, Bacterial/administration & dosage , Granuloma/immunology , Granuloma/pathology , Tuberculosis/immunology , Animals , Antibodies, Bacterial/blood , Bacterial Load , Disease Models, Animal , Female , Granuloma/blood , Granuloma/enzymology , Humans , Lung/microbiology , Lung/pathology , Matrix Metalloproteinase 9/metabolism , Mice , Necrosis , Recurrence , Tuberculosis/blood , Tuberculosis/enzymology , Tuberculosis/pathology
2.
Bioorg Med Chem Lett ; 24(3): 995-9, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24412072

ABSTRACT

The HIV protease inhibitor (PI) ritonavir (RTV) has been widely used as a pharmacoenhancer for other PIs, which are substrates of cytochrome P450 3A (CYP3A). However the potent anti-HIV activity of ritonavir may limit its use as a pharmacoenhancer with other classes of anti-HIV agents. Ritonavir is also associated with limitations such as poor physicochemical properties. To address these issues a series of compounds with replacements at the P2 and/or P3 region was designed and evaluated as novel CYP3A inhibitors. Through these efforts, a potent and selective inhibitor of CYP3A, GS-9350 (cobicistat) with improved physiochemical properties was discovered.


Subject(s)
Carbamates/chemistry , Cytochrome P-450 CYP3A Inhibitors , Diamines/chemistry , Diamines/pharmacology , Thiazoles/chemistry , Carbamates/pharmacology , Cobicistat , Enzyme Activation/drug effects , Molecular Structure , Structure-Activity Relationship , Thiazoles/pharmacology
3.
Bioorg Med Chem Lett ; 23(5): 1493-7, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23375792

ABSTRACT

A series of nevirapine-based analogues containing the phosphonate functionality were prepared and evaluated in vitro against HIV RT. The effect of the phosphonate was evaluated against the wild type and Y181C HIV replication. An in vivo PK study was performed on a select analogue.


Subject(s)
HIV Infections/drug therapy , Nevirapine/analogs & derivatives , Nevirapine/pharmacology , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , HIV-1/drug effects , Humans , Organophosphonates/chemistry , Reverse Transcriptase Inhibitors/chemistry , Structure-Activity Relationship
4.
Antimicrob Agents Chemother ; 56(10): 5409-13, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22850510

ABSTRACT

The experimental pharmacoenhancer cobicistat (COBI), a potent mechanism-based inhibitor of cytochrome P450 3A enzymes, was found to inhibit the intestinal efflux transporters P-glycoprotein and breast cancer resistance protein. Consistent with its transporter inhibition, COBI significantly increased the absorptive flux of potential candidates for clinical coadministration, including the HIV protease inhibitors atazanavir and darunavir and the lymphoid cell- and tissue-targeted prodrug of the nucleotide analog tenofovir, GS-7340, through monolayers of Caco-2 cells in vitro.


Subject(s)
Adenine/analogs & derivatives , Carbamates/pharmacology , HIV Protease Inhibitors/metabolism , Intestinal Absorption/drug effects , Thiazoles/pharmacology , Adenine/metabolism , Alanine , Caco-2 Cells , Cobicistat , Humans , Tenofovir/analogs & derivatives
5.
Antimicrob Agents Chemother ; 51(10): 3498-504, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17664327

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.


Subject(s)
Adenine/analogs & derivatives , HIV Protease Inhibitors/pharmacology , Intestinal Absorption/drug effects , Organophosphonates/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Adenine/pharmacokinetics , Caco-2 Cells , Cell Line , Chromatography, High Pressure Liquid , Data Interpretation, Statistical , Dose-Response Relationship, Drug , Drug Interactions , Epithelium/metabolism , Humans , Hydrolysis , Indicators and Reagents , Mass Spectrometry , Subcellular Fractions/drug effects , Subcellular Fractions/metabolism , Tenofovir
6.
Antivir Ther ; 12(2): 267-72, 2007.
Article in English | MEDLINE | ID: mdl-17503669

ABSTRACT

BACKGROUND: Active renal secretion of tenofovir (TFV) across proximal tubules occurs via uptake by human organic anion transporters 1 and 3 (hOAT1 and hOAT3) coupled with efflux by multidrug resistance protein 4 (MRP4). Co-administration of some HIV protease inhibitors (PIs) with tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, has been shown to increase systemic levels of TFV, leading to a hypothesis that PIs may affect tubular secretion of TFV and potentially alter the renal safety of TDF. METHODS: The effect of PIs on the transport of TFV by hOAT1, hOAT3 and MRP4 was assessed using in vitro cell-based transport models. RESULTS: At concentrations equal to their therapeutic peak plasma levels (Cmax) all PIs showed <20% inhibition of TFV transport by hOAT1. hOAT3 was more sensitive to Pls with ritonavir (RTV) and lopinavir being the most potent inhibitors of TFV transport (62% and 37% inhibition, respectively, at their Cmax). In the absence of human serum, RTV at concentrations exceeding its therapeutic Cmax also exhibited a minor effect on the cellular efflux of TFV by MRP4 (<30% inhibition at 20 microM). However, no effects of PIs on hOAT1, hOAT3 or MRP4 were detected in the presence of human serum with the exception of RTV that inhibited hOAT3 by approximately 35% at its Cmax. In addition, PIs did not affect the cytotoxicity of TFV or TDF in MRP4- or MRP2-overexpressing cells. CONCLUSION: These data indicate a low potential of PIs to interfere with the active tubular secretion of TFV and to alter the clinical renal safety profile of TDF.


Subject(s)
Adenine/analogs & derivatives , HIV Protease Inhibitors/pharmacology , Kidney/drug effects , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Organic Anion Transport Protein 1/antagonists & inhibitors , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Organophosphonates/metabolism , Reverse Transcriptase Inhibitors/metabolism , Adenine/metabolism , Adenine/toxicity , Animals , CHO Cells , Cell Survival , Cricetinae , Cricetulus , Dogs , Dose-Response Relationship, Drug , Drug Interactions , Humans , Inhibitory Concentration 50 , Kidney/cytology , Kidney/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Organic Anion Transport Protein 1/metabolism , Organic Anion Transporters, Sodium-Independent/metabolism , Organophosphonates/toxicity , Reverse Transcriptase Inhibitors/toxicity , Tenofovir , Time Factors , Transfection
7.
Antimicrob Agents Chemother ; 50(10): 3297-304, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17005808

ABSTRACT

Tenofovir (TFV) undergoes renal elimination by a combination of glomerular filtration and active tubular secretion. While transporter-mediated uptake of TFV from the blood into proximal-tubule cells has been well characterized, comparatively little is known about the efflux system responsible for transporting TFV into the lumen during active tubular secretion. Therefore, members of the ATP-binding cassette family of efflux pumps expressed at the apical side of proximal-tubule cells were studied for the ability to transport TFV. Studies in multiple independent in vitro systems show TFV not to be a substrate for P glycoprotein (Pgp) or multidrug resistance protein type 2 (MRP2). In contrast to Pgp and MRP2, TFV was observed to be a substrate for MRP4. TFV accumulated to fivefold lower levels in MRP4-overexpressing cells, and its accumulation could be increased by an MRP inhibitor. Furthermore, MRP4-overexpressing cells were found to be 2.0- to 2.5-fold less susceptible to cytotoxicity caused by TFV. ATP-dependent uptake of TFV was observed in membrane vesicles containing MRP4 but not in vesicles lacking the transporter. On the basis of these and previous results, the molecular transport pathway for the active tubular secretion of TFV through renal proximal-tubule cells involves uptake from the blood mediated by human organic anion transporters 1 and 3 and efflux into urine by MRP4. A detailed understanding of the molecular mechanism of TFV active tubular secretion will facilitate the assessment of potential renal drug-drug interactions with coadministered agents.


Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/pharmacokinetics , Kidney Tubules, Proximal/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Organophosphonates/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Adenine/pharmacokinetics , Animals , Cell Line , Cell Line, Tumor , Dogs , Humans , Organic Anion Transporters , Tenofovir
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