Human immunodeficiency virus-infected patients on antiretroviral drug therapy frequently experience hepatotoxicity, the underlying mechanism of which is poorly understood. Hepatotoxicity from other compounds such as bosentan and troglitazone has been attributed, in part, to inhibition of hepatocyte bile acid excretion. This work tested the hypothesis that antiretroviral drugs modulate hepatic bile acid transport. Ritonavir (28 M ϭ 2.1 and 6.4 M in human and rat, respectively), saquinavir (IC 50 ϭ 6.7 and 20 M, respectively), and efavirenz (IC 50 ϭ 43 and 97 M, respectively). Nevirapine (75 M) had no effect on bile acid transport in any model system. In conclusion, ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibited both the hepatic uptake and biliary excretion of taurocholate.

P-glycoprotein (Pgp) is a membrane bound transporter involved in the disposition of many endogenous compounds and xenobiotics. Alterations in Pgp expression and activity can significantly affect the disposition of Pgp substrates. Infection and inflammatory stimuli have also been shown to alter drug disposition. However, the specific effects of inflammation on Pgp expression and activity are not well understood. This paper evaluates and summarizes the current literature on the effects of cytokines and inflammation on mRNA and protein expression as well as functional activity of Pgp in whole animal models, primary rodent hepatocytes and human carcinoma cell lines.

The transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SCZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SCZ association findings. We identified 11 322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having ≥1 Ebox) and implicate a gene set enriched for genes downregulated in TCF4 small-interfering RNA (siRNA) knockdown experiments, indicating the validity of our findings. The TCF4 gene set was also enriched among (1) gene ontology categories such as axon/neuronal development, (2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex and (3) genes downregulated in postmortem brain tissue from SCZ patients (odds ratio, OR = 2.8, permutation P < 4x10-5). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA-binding proteins such as FOXP2 and the SCZ-associated EP300. TCF4 binding sites were modestly enriched among SCZ risk loci from the Psychiatric Genomic Consortium (OR = 1.56, P = 0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site ±10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. These findings confirm TCF4 as an important regulator of neural genes and point toward functional interactions with potential relevance for SCZ.

Study Objectives-To evaluate whether patients with human immunodeficiency virus (HIV) infection who were receiving protease inhibitor therapy had altered bile acid concentrations compared with noninfected control subjects, and whether bile acid concentrations could predict the onset of hepatotoxicity caused by protease inhibitors.Design-Retrospective sample analysis from a prospectively conducted clinical trial. Setting-Academic research center.Patients-Eleven adults with advanced HIV disease who were taking protease inhibitor-based antiretroviral therapy, one of whom had developed protease inhibitor-induced hepatotoxicity. Measurements and MainResults-Plasma concentrations of cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), and taurocholic acid (TC) were analyzed by using a novel highperformance liquid chromatography with tandem mass spectrometry detection method. Comparisons of the relative contribution of each bile acid to the total bile acid pool were made with previously published values and with bile acid concentrations contained in two pooled plasma samples from healthy, non-HIV-infected volunteers analyzed in our laboratory. Each pooled plasma sample used for this analysis contained contributions from three non-HIV-infected volunteers. The LCA and TC concentrations in HIV-infected patients were 3-4-fold higher than those previously reported for non-HIV-infected subjects; concentrations of other bile acids were similar to those of previous reports. The relative contribution of CDCA to the total bile acid pool was 9% in HIV-infected patients compared with 30-50% in noninfected subjects. Total and individual bile acid concentrations in the HIV-infected patient who developed hepatotoxicity were similar to the bile acid concentrations from the other study patients who did not develop hepatotoxicity.Conclusion-These data suggest that bile acid concentrations may be altered by HIV infection and/or protease inhibitor therapy. However, further investigations should be performed to assess whether antiretroviral-associated hepatotoxicity can be predicted by alterations in individual bile acid concentrations. Recently, we published the results of a clinical investigation conducted in 11 human immunodeficiency virus (HIV)-infected patients on the pharmacokinetics, safety, and efficacy of an antiretroviral regimen that included three protease inhibitors: amprenavir, ritonavir, and saquinavir. 14 During that study, drug-induced hepatotoxicity was diagnosed in one of the 11 patients. In this current study, we used blood samples obtained from that study to determine whether the average plasma concentrations of individual bile acids of HIVinfected patients differ compared with a population of non-HIV-infected individuals, whether protease inhibitor therapy influences bile acid concentrations during a dosing interval, and whether elevations in total or individual plasma bile acid concentrations might be an early signal of drug-induced hepat...

Background 2009 H1N1 influenza A disproportionately affected pregnant and postpartum women compared to the general population with higher rates of hospitalization and severe illness. The purpose of this study was to examine the use and pharmacokinetics of intravenous peramivir in the treatment of a newly postpartum patient with severe influenza. Case A 28-year-old, 37 week pregnant (G4,P3) woman presented to the hospital with severe respiratory symptoms. 2009 H1N1 influenza RT-PCR returned positive and intravenous peramivir was started. She showed rapid improvement and was discharged 29 days following admission. Conclusion The pharmacokinetic parameters for this case patient were unexpected based on previously reported pharmacokinetic parameters from phase 1 trials. These differences highlight the need for additional pharmacokinetic reporting of peramivir in pregnant and postpartum patients.