scholarly journals Cobicistat Boosts the Intestinal Absorption of Transport Substrates, Including HIV Protease Inhibitors and GS-7340,In Vitro

2012 ◽  
Vol 56 (10) ◽  
pp. 5409-5413 ◽  
Author(s):  
Eve-Irene Lepist ◽  
Truc K. Phan ◽  
Anupma Roy ◽  
Leah Tong ◽  
Kelly MacLennan ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Cancer Resistance ◽  
Cytochrome P450 3A ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Absorptive Flux ◽  
Intestinal Efflux

ABSTRACTThe 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 cellsin vitro.

scholarly journals P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β

2009 ◽  
Vol 29 (6) ◽  
pp. 1079-1083 ◽  
Author(s):  
Leon M Tai ◽  
A Jane Loughlin ◽  
David K Male ◽  
Ignacio A Romero
Keyword(s):  
Breast Cancer ◽  
Human Brain ◽  
Breast Cancer Resistance Protein ◽  
Amyloid Β ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
The Brain

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.

Oleic acid increases uptake and decreases the P-gp-mediated efflux of the veterinary anthelmintic Ivermectin

Drug Research ◽  
2018 ◽  
Vol 69 (03) ◽  
pp. 173-180 ◽  
Author(s):  
Bilal Houshaymi ◽  
Nadine Nasreddine ◽  
Mamdouh Kedees ◽  
Zeina Soayfane
Keyword(s):  
Oleic Acid ◽  
Intestinal Mucosa ◽  
Drug Formulation ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Complex Micelles

AbstractThe bioavailability of ivermectin is modulated by lipid-based formulations and membrane efflux transporters such as Breast Cancer Resistance Protein and P-glycoprotein (BCRP and P-gp). We have investigated the effect of oleic acid on the uptake of ivermectin in vitro using Caco-2 cells and in vivo in the intestines of wild-type mice. Complex micelles (M) with oleic acid induced a significant increase (e. g. for M3 was 7-fold, p≤0.001) in the uptake of the drug in a time-dependent manner with no involvement of cholesterol in the mechanism. In vivo results showed a significant increase in the concentration of plasma and intestinal mucosa ivermectin (p≤0.01) in mice receiving oleic acid-based drug formulation. We also examined the expression of the drug efflux transporter, BCRP and P-gp in Caco-2 cells and found a significant decrease (p≤0.001) in their level in the presence of 5 mM oleic acid. Treatment of mice with oleic acid-based formulation showed a significant decrease in the activity of P-gp in the intestinal mucosa (p≤0.01). This study highlighted the effect of oleic acid in decreasing the expression and the activity of P-gp-mediated ivermectin efflux and in limiting the drug absorption by increasing its uptake and bioavailability in Caco-2 cells and intestine, respectively.

IN VITRO INHIBITION OF UDP GLUCURONOSYLTRANSFERASES BY ATAZANAVIR AND OTHER HIV PROTEASE INHIBITORS AND THE RELATIONSHIP OF THIS PROPERTY TO IN VIVO BILIRUBIN GLUCURONIDATION

2005 ◽  
Vol 33 (11) ◽  
pp. 1729-1739 ◽  
Author(s):  
Donglu Zhang ◽  
Theodore J. Chando ◽  
Donald W. Everett ◽  
Christopher J. Patten ◽  
Shangara S. Dehal ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
In Vitro Inhibition ◽  
Relationship Of ◽  
The Relationship

scholarly journals Atazanavir Signature I50L Resistance Substitution Accounts for Unique Phenotype of Increased Susceptibility to Other Protease Inhibitors in a Variety of Human Immunodeficiency Virus Type 1 Genetic Backbones

2005 ◽  
Vol 49 (9) ◽  
pp. 3816-3824 ◽  
Author(s):  
S. Weinheimer ◽  
L. Discotto ◽  
J. Friborg ◽  
H. Yang ◽  
R. Colonno
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Treatment Options ◽  
Hiv Infections ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Protease Inhibition ◽  
Immunodeficiency Virus ◽  
Increased Susceptibility

ABSTRACT Substitution of leucine for isoleucine at residue 50 (I50L) of human immunodeficiency virus (HIV) protease is the signature substitution for atazanavir (ATV) resistance. A unique phenotypic profile has been associated with viruses containing the I50L substitution, which produces ATV-specific resistance and increased susceptibility to most other approved HIV protease inhibitors (PIs). The basis for this unique phenotype has not been clearly elucidated. In this report, a direct effect of I50L on the susceptibility to the PI class is described. Cell-based protease assays using wild-type and PI-resistant proteases from laboratory and clinical isolates and in vitro antiviral assays were used to demonstrate a strong concordance between changes in PI susceptibility at the level of protease inhibition and changes in susceptibility observed at the level of virus infection. The results show that the induction of ATV resistance and increased susceptibility to other PIs by the I50L substitution is likely determined at the level of protease inhibition. Moreover, the I50L substitution functions to increase PI susceptibility even in the presence of other primary and secondary PI resistance substitutions. These findings may have implications regarding the optimal sequencing of PI therapies necessary to preserve PI treatment options of patients with ATV-resistant HIV infections.

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