ABSTRACT:Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clinical DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.Pharmacokinetic drug-drug interactions (DDIs) can occur when one drug alters the metabolism of a coadministered drug. The outcome is an increase or decrease in the systemic clearance and/or bioavailability, and a corresponding change in the exposure to a coadministered drug. The clinical consequences of DDIs range from lack of therapeutic efficacy of a life saving drug to severe adverse drug reactions, including fatalities. Significant drug-drug interactions can lead to termination of development of otherwise promising new therapies, withdrawal of a drug from the market, or severe restrictions/limitations on its use (Wienkers and Heath, 2005). Because of the impact on patient health and safety, DDI was the subject of a position paper in 2003 by scientists from member companies of the Pharmaceutical Research and Manufacturers of America (PhRMA) that focused on Article, publication date, and citation information can be found at
A series of adsorption tests were performed on material used in the construction of a clay‐lined fly‐ash waste pile at a lignite‐burning power plant in Texas to determine which soil component is the most effective in adsorbing selenium. Selenium, in the form of selenite, is adsorbed by hydrous iron oxides to a greater extent than selenite adsorbed by clays chemically treated to remove organics and free iron. In natural systems, clays will be coated by iron oxides and organic material, and these coatings may prevent anions like HSeO−3 and SeO−23 from sorbing onto positive exchange sites of clay surfaces. However, anions can be effectively adsorbed by these highly reactive surface coatings. Thus, the efficacy of clay as an adsorption medium may be overestimated in construction of environmental barriers for retention of elements like selenium.
Five hundred financial institutions in the United States are randomly sampled each year in order to examine Internet participation present and planned by the financial institutions. Each year CEOs of selected institutions are asked about the institutions present involvement with on?line banking and their internet plans for the next two years. The usable response rates achieved in these studies have exceeded 40 percent. This paper examines the responses for the year 2001.
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