Correlations between atazanavir Ctrough and hyperbilirubinemia: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hyperbilirubinemia is a common side effect of the antiretroviral agent atazanavir but is generally reversible upon discontinuation of treatment. We used therapeutic drug monitoring to investigate the occurrence of hyperbilirubinemia in a 49-year-old Hispanic man infected with HIV, following an overdose of ritonavir in ritonavir-boosted atazanavir therapy.</p> <p>Case presentation</p> <p>A 49-year-old Hispanic man with HIV who had received several highly active antiretroviral therapy regimens over a number of years including atazanavir-containing regimens, was diagnosed with hyperbilirubinemia. An inappropriate doubling of ritonavir boosting resulted in a high atazanavir C_troughand an initial rise in bilirubin plasma levels. Bilirubin levels later decreased, probably as a consequence of enzyme induction, while atazanavir plasma concentrations remained elevated.</p> <p>Conclusion</p> <p>This article describes an occurrence of hyperbilirubinemia in a man infected with HIV and supports the importance of therapeutic drug monitoring in investigations of hyperbilirubinemia among patients receiving antiretroviral agents. That the patient tolerated exceptionally high atazanavir levels further strengthens the tolerability profile of this drug.</p

Chemical–Genetic Profiling of Imidazo[1,2-a]pyridines and -Pyrimidines Reveals Target Pathways Conserved between Yeast and Human Cells

Small molecules have been shown to be potent and selective probes to understand cell physiology. Here, we show that imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines compose a class of compounds that target essential, conserved cellular processes. Using validated chemogenomic assays in Saccharomyces cerevisiae, we discovered that two closely related compounds, an imidazo[1,2-a]pyridine and -pyrimidine that differ by a single atom, have distinctly different mechanisms of action in vivo. 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine was toxic to yeast strains with defects in electron transport and mitochondrial functions and caused mitochondrial fragmentation, suggesting that compound 13 acts by disrupting mitochondria. By contrast, 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine acted as a DNA poison, causing damage to the nuclear DNA and inducing mutagenesis. We compared compound 15 to known chemotherapeutics and found resistance required intact DNA repair pathways. Thus, subtle changes in the structure of imidazo-pyridines and -pyrimidines dramatically alter both the intracellular targeting of these compounds and their effects in vivo. Of particular interest, these different modes of action were evident in experiments on human cells, suggesting that chemical–genetic profiles obtained in yeast are recapitulated in cultured cells, indicating that our observations in yeast can: (1) be leveraged to determine mechanism of action in mammalian cells and (2) suggest novel structure–activity relationships