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Drug Metabolism Studies (drug + metabolism_studies)
Selected AbstractsElectrochemical, Chemical and Enzymatic Oxidations of PhenothiazinesELECTROANALYSIS, Issue 17 2005B. Blankert Abstract The oxidation of several phenothiazine drugs (phenothiazine, promethazine hydrochloride, promazine hydrochloride, trimeprazine hydrochloride and ethopropazine hydrochloride) has been carried out in aqueous acidic media by electrochemical, chemical and enzymatic methods. The chemical oxidation was performed in acetic acid with hydrogen peroxide or in formate buffers using persulfate. The enzymatic oxidation was performed in acetate or ammonium formate buffer by the enzyme horseradish peroxidase in the presence of H2O2. Molecules with, in the lateral chain, two carbon atoms (2C) separating the ring nitrogen and the terminal nitrogen, showed two parallel oxidation pathways, that is (i) formation of the corresponding sulfoxide and (ii) cleavage of the lateral chain with liberation of phenothiazine (PHZ) oxidized products (PHZ sulfoxide and PHZ quinone imine). Molecules with three carbon atoms (3C) separating the two nitrogens were oxidized to the corresponding sulfoxide. The chemical oxidation of all the studied molecules by hydrogen peroxide resulted in the corresponding sulfoxide with no break of the lateral chain. Oxidation by persulfate yielded, for the 3C derivatives, only the corresponding sulfoxide, but it produced cleavage of the lateral chain for the 2C derivatives. The origin of the distinct oxidation pattern between 2C and 3C molecules might be related to steric effects due to the lateral chain. The data are of interest in drug metabolism studies, especially for the early search. In the case of 2C phenothiazines, the results predict the possibility of an in vivo cleavage of the lateral chain with liberation of phenothiazine oxidized products which are known to produce several adverse side effects. [source] Extracting metabolite ions out of a matrix background by combined mass defect, neutral loss and isotope filtrationRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 2 2009Filip Cuyckens Mass defect, neutral loss and isotope filtration techniques were applied to electrospray ionization mass spectrometry (ESI-MS) data obtained for in vivo and in vitro samples of drug metabolism studies. A combination of these post-acquisition processing techniques was shown to be more powerful than the use of one of these tools alone for the detection in complex matrices of metabolites of candidate drugs with a characteristic isotope pattern (e.g. containing bromine, chlorine, or a high proportion of radiolabeled drug (12C/14C)) or characteristic neutral losses. In combination with ,all-in-one' data acquisition this methodology is able to perform software-driven constant neutral loss scanning for an unlimited number of mass differences at any time after analysis. Highly selective MS chromatograms were obtained with excellent correlation with their corresponding radiochromatograms. Copyright © 2009 John Wiley & Sons, Ltd. [source] Liquid chromatography/tandem mass spectrometric quantification with metabolite screening as a strategy to enhance the early drug discovery processRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 12 2002Philip R. Tiller Throughput for early discovery drug metabolism studies can be increased with the concomitant acquisition of metabolite screening information and quantitative analysis using ultra-fast gradient chromatographic methods. Typical ultra-fast high-performance liquid chromatography (HPLC) parameters used during early discovery pharmacokinetic (PK) studies, for example, employ full-linear gradients over 1,2,min at very high flow rates (1.5,2,mL/min) on very short HPLC columns (2,×,20,mm). These conditions increase sample throughput by reducing analytical run time without sacrificing chromatographic integrity and may be used to analyze samples generated from a variety of in vitro and in vivo studies. This approach allows acquisition of more information about a lead candidate while maintaining rapid analytical turn-around time. Some examples of this approach are discussed in further detail. Copyright © 2002 John Wiley & Sons, Ltd. [source] Evaluation of SupermixTM as an in vitro model of human liver microsomal drug metabolismBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2002Karthik Venkatakrishnan Abstract SUPERMIXTM is a commercially available formulation of insect cell-expressed human drug-metabolizing cytochrome P450 (CYP) isoforms, mixed in proportions that are optimized to parallel their relative activities in human liver microsomes. We have evaluated the apparent functional affinity and capacity of individual CYP isoforms in SUPERMIXTM in comparison with microsomes from a panel of 12 human livers, using enzyme kinetic studies of isoform-selective index reactions. In addition, we have measured the concentration of NADPH cytochrome P450 oxidoreductase (OR) in SUPERMIXTM and compared it with the concentrations of this accessory electron transfer protein in human liver microsomes. No important differences were evident in the catalytic activities of CYPs 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 between SUPERMIXTM and human liver microsomes. However, SUPERMIXTM lacks CYP2B6 activity and did not hydroxylate the antidepressant bupropion, a clinically relevant substrate of this enzyme. In addition, the concentration of OR in SUPERMIXTM (1198 pmol mg protein,1) is 17-fold higher than the mean value in human liver microsomes (70 pmol mg protein,1). In conclusion, SUPERMIXTM lacks CYP2B6 activity and contains supraphysiological concentrations of the accessory electron transfer protein OR. These factors should be considered when this formulation is used as an in vitro model in human liver microsomal drug metabolism studies. Copyright © 2002 John Wiley & Sons, Ltd. [source] | ||||||||||