Advancement of in silico tools would be enabled by the availability of data for metabolic reaction rates and intrinsic clearance (CL int ) of a diverse compound structure data set by specific metabolic enzymes. Our goal is to measure CL int for a large set of compounds with each major human cytochrome P450 (P450) isozyme. To achieve our goal, it is of utmost importance to develop an automated, robust, sensitive, high-throughput metabolic stability assay that can efficiently handle a large volume of compound sets. The substrate depletion method [in vitro half-life (t 1/2 ) method] was chosen to determine CL int . The assay (384-well format) consisted of three parts: 1) a robotic system for incubation and sample cleanup; 2) two different integrated, ultraperformance liquid chromatography/mass spectrometry (UPLC/MS) platforms to determine the percent remaining of parent compound, and 3) an automated data analysis system. The CYP3A4 assay was evaluated using two long t 1/2 compounds, carbamazepine and antipyrine (t 1/2 > 30 minutes); one moderate t 1/2 compound, ketoconazole (10 < t 1/2 < 30 minutes); and two short t 1/2 compounds, loperamide and buspirone (t ½ < 10 minutes). Interday and intraday precision and accuracy of the assay were within acceptable range (∼12%) for the linear range observed. Using this assay, CYP3A4 CL int and t 1/2 values for more than 3000 compounds were measured. This high-throughput, automated, and robust assay allows for rapid metabolic stability screening of large compound sets and enables advanced computational modeling for individual human P450 isozymes.

The introduction of electrospray ionization mass spectrometry (ESI-MS) in the mid-1980s started a new era in mass spectrometry and, currently, mass spectrometers of this type are present in virtually all pharmaceutical and biotechnology laboratories. Mass spectrometry has now become important for obtaining molecular weights as well as structural information for chemical substances including very large molecules, for example, biological substances such as proteins, carbohydrates, and oligonucleotides. This paper extends the applications of ESI-MS in this series to a variety of inorganic systems.

SYNOPSISExtensive research has been carried out in recent years using fluorocarbon plasmas for modification and depositions on polymer substrates. In some cases anomalous results have been obtained that are not explainable based on conventional fluorine chemistry. In this investigation pure polypropylene films were exposed to carbon tetrafluoride plasmas in a Pyrex glass reactor. A t short reaction times (less than 1 min) significant amount of silicon was detected by ESCA on the surface of the films. Analysis of liquid nitrogen trapped fluorocarbon plasma gases and molecular fragments indicated high concentrations of silicon and carbon containing species, the former indicative of ablation and etching reactions of the glass reactor walls. The production of a relatively high quantity of fluorosilicon derivatives was explained by the greater affinity of silicon for fluorine than for carbon, with the tendency to readily form SiF,. These fluorosilicon radical and ionic species generated under cold plasma conditions can easily react with polymeric substrates causing unexpected surface modifications. In addition Si-F bonds could be readily hydrolyzed to SiOH islands on the surface of the substrate to impart anomalous characteristics.

SYNOPSISThere has been an increasing interest in depositing metal or metal-containing thin films through plasma polymerization for various applications. This work deals with the plasma graft polymerization of tetramethyltin (TMT) on polypropylene surfaces with an aim of producing special electrical and optical coatings. The fragmentation of TMT under cold plasma conditions and the recombination of discharge-generated active species were studied by analyzing the resulting molecular mixture trapped outside of the plasma zone by HR-MS and GC-MS techniques. It was found that the predominant ionic fragment is m/z = 165, and the most probable intermediate structure of the polymer formation mechanism is hexamethylditin. The structure of polymeric layers deposited on various substrates were investigated by ESCA and FT-IR methods. Intense oxidation of tin-based polymeric layers were observed under open laboratory conditions. The existence of weak Sn-Sn and Sn-C bonds in the polymeric structures is suggested to be responsible for this reaction. This phenomenon was associated with enhanced UV transparency. Based on analytical data a plasma-enhanced polymerization mechanism of TMT is proposed. 0 1995 John Wiley & Sons, Inc.

ChemInform Abstract Addition of an acidified Fe(NO3)3 solution at constant pH (pH 6) to a suspension of the support results in the deposition of highly dispersed α-FeOOH. The reduction of Fe/Al2O3 occurs in the sequence α-FeOOH → Fe3O4 → Fe1-xO → α-Fe (particles of 20-30 nm diameter after 15 h at 873 K). It is shown that the catalyst surface still contains traces of oxygen after reduction. The reduction of Fe/SiO2 proceeds via an Fe(II)-silicate which is partly reduced to α-Fe at higher temperatures. The iron crystallites appear to be partly encapsulated by an Fe(II)-silicate layer. The encapsulation of SiO2-supported Fe particles, the incomplete reduction of the Al2O3-supported iron, and the reoxidation occurring upon high-temp. evacuation presumably account for the small extent of room temp. hydrogen chemisorption usually observed for supported iron catalyst.