What Is Already Known About This Subject: * The viral protease inhibitor ritonavir is known to inhibit clearance of intravenous midazolam. * ALT-2074, a catalytic mimic of glutathione oxidase, inhibits human cytochrome P450 3A (CYP3A) isoforms in vitro.
What This Study Adds: * Short-term administration of low-dose ritonavir increases area under the plasma concentration curve following oral midazolam by a factor of 28.
J Acquir Immune Defic Syndr
December 2008
Purpose: Ritonavir is a powerful inhibitor of cytochrome P450 3A (CYP3A) that metabolizes many antiretrovirals. We examined the effect of ritonavir and of chronic viral hepatitis (CVH) status on CYP3A activity.
Methods: Twenty-six HIV-positive men (13 with CVH, 16 on chronic ritonavir-based highly active antiretroviral therapy) received oral and intravenous midazolam, a probe for CYP3A phenotypic activity.
Glucuronidation studies using microsomes and recombinant uridine diphosphoglucuronosyltransferases (UGTs) can be complicated by the presence of endogenous beta-glucuronidases, leading to underestimation of glucuronide formation rates. Saccharolactone is the most frequently used beta-glucuronidase inhibitor, although it is not clear whether this reagent should be added routinely to glucuronidation incubations. Here we have determined the effect of saccharolactone on eight different UGT probe activities using pooled human liver microsomes (pHLMs) and recombinant UGTs (rUGTs).
View Article and Find Full Text PDFThe effect of pomegranate juice (PJ) or grapefruit juice (GFJ) on CYP3A activity was studied in vitro and in healthy human volunteers. In human liver microsomes, the mean 50% inhibitory concentrations (IC(50)) for PJ and GFJ versus CYP3A (triazolam alpha-hydroxylation) were 0.61% and 0.
View Article and Find Full Text PDFCorticotropin-releasing hormone (CRH) is secreted under stress and regulates the hypothalamic-pituitary-adrenal (HPA) axis; it is also secreted outside the brain where it exerts proinflammatory effects, possibly through mast cell activation. Mast cells are necessary for allergic reactions, but are increasingly implicated in acquired immunity and inflammatory diseases worsened by stress. Acute stress and intradermal CRH induced murine skin mast cell activation and increased vascular permeability that was absent in W/W(v) mast cell deficient mice.
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