raltegravir-potassium and vicriviroc

The chemokine receptor antagonists maraviroc and vicriviroc and the integrase inhibitors elvitegravir and raltegravir are novel antiretroviral agents for the treatment of HIV-1 infections. ATP-binding cassette (ABC) transporters as modulators of the effectiveness and safety of therapy can mediate viral resistance and drug-drug interactions. To expand knowledge on drug-drug interactions of these antiretrovirals we investigated whether these compounds are substrates, inhibitors or inducers of important ABC transporters.. We evaluated P-glycoprotein (P-gp/ABCB1) inhibition by the calcein assay in P388/dx and L-MDR1 cells, breast cancer resistance protein (BCRP/ABCG2) inhibition in MDCKII-BCRP cells by pheophorbide A efflux, and inhibition of the multidrug resistance-associated protein 2 (MRP2/ABCC2) by using the MRP2 PREDIVEZ™ Vesicular Transport Kit. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC transporters. Induction of transporters was quantified by real-time RT-PCR in LS180 cells and for ABCB1 also at the functional level.. Elvitegravir and vicriviroc inhibited ABCB1 in P388/dx and L-MDR1 cells (f2 values 1.9±0.2 µmol/L and 8.5±3.6 µmol/L, respectively). The IC50 for ABCG2 inhibition was 15.7±5.7 µmol/L for elvitegravir and 236.7±93.3 µmol/L for vicriviroc. Raltegravir and maraviroc showed no evidence of ABCB1 or ABCG2 inhibition. Maraviroc and vicriviroc stimulated ABCC2 transport function. Growth inhibition assays suggest that elvitegravir, raltegravir and vicriviroc are substrates of ABCB1. Induction assays demonstrate that mRNA expression of several ABC transporters is induced by these antiretrovirals in LS180 cells.. The new antiretrovirals bear the potential to modulate expression and function of several ABC transporters, with elvitegravir revealing the highest interaction potential.

Topics: Animals; Anti-Retroviral Agents; ATP-Binding Cassette Transporters; Biological Transport; Cell Line; Cell Survival; Cyclohexanes; Dogs; Gene Expression Profiling; Maraviroc; Piperazines; Pyrimidines; Pyrrolidinones; Quinolones; Raltegravir Potassium; Triazoles

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclohexanes; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Maraviroc; Piperazines; Pyrimidines; Pyrrolidinones; Quinolones; Raltegravir Potassium; Succinates; Triazoles; Triterpenes; Viral Load

The XVI International AIDS Conference (AIDS 2006), organized by the International AIDS Society (IAS), took place August 12-18 in Toronto, Canada. It was attended by over 26,000 participants from more than 170 countries and featured more than 4,500 abstracts as well as an array of community and cultural activities. The theme of the meeting was "Time to deliver", emphasizing the continued need and urgency in bringing effective HIV prevention and treatment strategies to those living with and affected by HIV/AIDS. The meeting's agenda was broad and included policy and programmatic topics as well as scientific research. This report focuses on reports presented at the conference that directly deal with antiretroviral therapy. This is primarily because of the nature of the venue where it is intended to be published (Drug News & Perspectives) as well as the expertise of the author. It is not a lack of recognition of the other equally important topics and discussions that took place at AIDS 2006. The author is solely responsible for the selection of topics and presentations to be included in this report.

Topics: Anti-HIV Agents; Anti-Retroviral Agents; Antibodies, Monoclonal; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Cyclohexanes; Darunavir; Drugs, Investigational; HIV Infections; HIV-1; Humans; Maraviroc; Nitriles; Organic Chemicals; Piperazines; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Receptors, Chemokine; Sulfonamides; Treatment Outcome; Triazoles