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11.
Analysis of caffeine and its metabolites is of interest with respect to caffeine exposure, for kinetic and metabolism studies and for opportunistic in vivo estimation of drug metabolizing enzyme activity in humans and animals. For the latter, analysis is usually done by high-performance liquid chromatography (HPLC) with UV detection. However, this method is close to the detection limit for certain of the metabolites and requires very long chromatography, 30-60 min. We have developed a fast method for the quantification of caffeine and its metabolites 1-methylxanthine, 1-methyluric acid, 1,7-dimethyluric acid, 5-acetylamino-6-amino-3-methyluracil (AAMU) and 5-acetylamino-6-formylamino-3-methyluracil (AFMU) by HPLC tandem mass spectrometry (MS/MS) in urine that requires only its dilution with buffer and centrifugation before injection into the HPLC/MS/MS system. The chromatography lasts 7 min and is followed by 4.5 min for re-equilibration of the HPLC column, giving a total analysis time of 11.5 min. The method provides a great sensitivity improvement with detection limits for all analytes 相似文献
12.
X. Liu F. Xu Y. Zhang L. Liu H. Huang X. Cai Y. Lin W. Chan 《Russian Chemical Bulletin》2006,55(6):1091-1092
(3R*,3aR*,9aR*)-3,9a-Dimethyl-2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromene-5,7-diol (xyloketal H), a representative of a new family of xyloketals, was isolated from the marine-derived mangrove
fungus Xylaria sp. 2508. Its structure was elucidated by spectroscopic data and single-crystal X-ray diffraction analysis.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1051–1052, June, 2006. 相似文献
13.
Svein G. Dahl Peter A. Kollman Shashidhar N. Rao U. Chandra Singh 《Journal of computer-aided molecular design》1992,6(3):207-222
Summary The side-chain conformations of psychoactive phenothiazine drugs in crystals are different from those of biologically inactive ring sulfoxide metabolites. This study examines the potential energies, molecular conformations and electrostatic potentials in chlorpromazine, levomepromazine (methotrimeprazine), their sulfoxide metabolites and methoxypromazine. The purpose of the study was to examine the significance of the different crystal conformations of active and inactive phenothiazine derivatives, and to determine why phenothiazine drugs lose most of their biological activity by sulfoxidation. Quantum mechanics and molecular mechanics calculations demonstrated that conformations with the side chain folded over the ring structure had lowest potential energy in vacuo, both in the drugs and in the sulfoxide metabolites. In the sulfoxides, side chain conformations corresponding to the crystal structure of chlorpromazine sulfoxide were characterized by stronger negative electrostatic potentials around the ring system than in the parent drugs. This may weaken the electrostatic interaction of sulfoxide metabolites with negatively charged domains in dopamine receptors, and cause the sulfoxides to be virtually inactive in dopamine receptor binding and related pharmacological tests. 相似文献
14.
The actual mobilities and dissociation constants of acidic and basic pharmaceuticals were determined in methanol. Actual mobilities were derived from the dependence of the effective mobilities of the analytes on the pH of the methanolic background electrolyte solution (pH(MeOH)). The pKa values of the pharmaceuticals in methanol (pK(a,MeOH)) were calculated by non-linear curve fitting to the measured mobility values. It was found that the shift in pKa value (when compounds were transferred from water to methanol) increased with the acidity of the analyte. The average pKa shift for compounds exhibiting acidic properties in water was ca. 5.5 units, and the shift for basic compounds about 2 units. As was shown for a mixture of beta-blockers, the calculated actual mobilities and pKa values can be utilised in the optimisation of pH conditions for separation. The practical value of the method was illustrated by the analysis of urine samples. 相似文献
15.
Samuel K Yin W Stearns RA Tang YS Chaudhary AG Jewell JP Lanza T Lin LS Hagmann WK Evans DC Kumar S 《Journal of mass spectrometry : JMS》2003,38(2):211-221
Metabolic activation of drug candidates to electrophilic reactive metabolites that can covalently modify cellular macromolecules may result in acute and/or idiosyncratic immune system-mediated toxicities in humans. This presents a significant potential liability for the future development of these compounds as safe therapeutic agents. We present here an example of an approach where sites of metabolic activation within a new drug candidate series were rapidly identified using online liquid chromatography/multi-stage mass spectrometry on an ion trap mass spectrometer. This was accomplished by trapping the reactive intermediates formed upon incubation of compounds with rat and human liver microsomes as their corresponding glutathione conjugates and mass spectral characterization of these thiol adducts. Based on the structures of the GSH adducts identified, potential sites and mechanisms of bioactivation within the chemical structure were proposed. These metabolism studies were interfaced with iterative structural modifications of the chemical series in order to block these bioactivation sites within the molecule. This strategy led to a significant reduction in the propensity of the compounds to undergo metabolic activation as evidenced by reductions in the irreversible binding of radioactivity to liver microsomal material upon incubation of tritium-labeled compounds with this in vitro system. With the efficiency and throughput achievable with such an approach, it appears feasible to identify and address the metabolic activation potential of new drug leads during routine metabolite identification studies in an early drug discovery setting. 相似文献
16.
Summary The feasibility of using columns prepared by mixing together ion exchange and reversed-phase packing materials, for the simultaneous separation of ionised and unionised molecules, has been examined using a range of test solutes. Columns prepared in this way showed chromatographic properties which were intermediate between those of the individual phases. The dual nature of the retention mechanism allowed the retention of ionisable molecules to be adjusted using pH whilst that of uncharged compounds was unaffected. The simultaneous chromatography of model compounds and their glucuronide, sulphate and glycine conjugates, under a variety of conditions, was demonstrated. 相似文献
17.
Hans-Detlev?GilsingEmail author Jürgen?Angerer Dietrich?Prescher 《Monatshefte für Chemie / Chemical Monthly》2005,136(5):795-801
Summary. The synthesis of an oxidative major metabolite of bis(2-ethylhexyl) phthalate is described. The target molecule and its ring-deuterated isomer were obtained via acylation of the appropriate -hydroxy benzyl ester or the corresponding carboxylate with phthalic anhydride or phthalic anhydride-d4. All transformation steps proceed with high yields. 相似文献
18.
The structure of the strongly cytotoxic marine alkaloid halitulin (1) has been confirmed by total synthesis and its absolute configuration determined as (15S). The synthesis follows a strategy previously reported by one of us and uses an efficient preparation of the quinoline-7,8-diol unit by modified Baeyer-Villiger and Skraup reactions. The O-benzyl protecting groups were removed in the last step of the synthesis by transfer hydrogenolysis without concomitant reduction of the quinoline ring. The method can be applied for the synthesis of halitulin analogues. 相似文献
19.
Traceability of the measurement of analytical parameters capable of evaluating the performance of methods is an important
concept for the assessment of quality for the routine control, especially for residue monitoring of non-authorized medicinal
substances in food from animal origin. The European Decision no. 657/2002/EC recommends to calculate two statistical limits,
CCα and CCβ, which allow to evaluate the critical concentrations above which the method reliably distinguish and quantify
a substance taking into account the variability of the method and the statistical risk to take a wrong decision. The calculation,
which can be derived from the ISO standard no. 11843 is applied on a routine basis. An example displays a very simple way
for evaluating the performance of an LC-MSMS method which has been validated a few years ago and is qualified onto a Micromass
Quattro LCZ tandem mass spectrometer to monitor and confirm the nitrofuran metabolite residues in food from animal origin.
Community Reference Laboratory for Antimicrobial Veterinary Drug Residue Control in Food from Animal Origin 相似文献
20.
G. Tamai H. Yoshida H. Imai T. Takashina K. Kotoo T. Fuwa Y. Tsuchioka H. Matsuura G. Kajiyama 《Chromatographia》1985,20(11):671-676
Summary New quinidine metabolites, including 10,11-dihydrodiol quinidine N-oxide, 10,11-dihydrodiol quinidine and their glucuronides, were found in human urine. A quinidine monitoring HPLC method including these metabolites, is proposed by the direct injection of body fluid samples onto the precolumn for deproteinization followed by reverse phase separation in the analytical column with a column switching technique. The recovery of spiked quinidine and its metabolites in plasma was quantitative (98–102%) with good reproducibility (C.V.: 1.6–4.0%). Several clinical samples such as whole blood and urine were analyzed by the present method. 相似文献