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Publications (3)7.26 Total impact

  • César Ramírez-Molina · Olivier Heudi · Mark Pullen · Peter S Marshall
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    ABSTRACT: The coupling of the techniques, high-performance liquid chromatography (HPLC), orthogonal acceleration time-of-flight mass spectrometry (OATOF-MS) and inductively coupled plasma mass spectrometry (ICP-MS) provides a very powerful method for identifying and quantifying the products of bradykinin metabolism. In this study, we were able to identify the major metabolites of bradykinin degradation reported in the literature. In addition, a new bradykinin metabolite corresponding to bradykinin 5,9 fragment (BK-(5,9)-fragment) was identified as a product of neutral endopeptidase (NEP) activity. This finding establishes that NEP cleaves bradykinin simultaneously at the positions 4-5 and 7-8. We also demonstrate the equivalent participation of NEP and angiotensin-converting enzyme (ACE) within the rat lung tissue membranes (RLTM) in bradykinin degradation, suggesting its suitability as a model for the assay of dual ACE/NEP inhibitors. On the contrary, in rat kidney brush border membranes (KBBM), ACE is not significantly involved in bradykinin metabolism, with NEP being the major enzyme.
    No preview · Article · Mar 2006 · Journal of Peptide Science
  • Peter S Marshall · Bill Leavens · Olivier Heudi · Cesar Ramirez-Molina
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    ABSTRACT: Both LC and capillary LC (CapLC) have been successfully interfaced with inductively coupled plasma mass spectrometry (ICP-MS). Gradients of acetonitrile and aqueous based solvents have been employed to separate several compounds of pharmaceutical interest. This paper will describe four application areas in the pharmaceutical industry, and examples will be shown where CapLC, LC and gel electrophoresis via laser ablation have been coupled with ICP-MS. The four areas highlighted in this paper are: (1) the use of derivatisation reactions to "make the invisible visible". Methods involving derivatisations with copper and iron will be described that can be used for the analysis of amines and carboxylic acids by ICP-MS. (2) The profiling of metal ion content (in particular bromine) in biological samples such as human plasma, this study will focus on the metabolism of bromine-labelled peptides (e.g. substance P). (3) The analysis of materials derived from single, solid-phase beads used in combinatorial chemistry, and (4) also discussed will be our findings from investigations into the use of laser ablation ICP-MS on the determination of protein phosphorylation on electrophoresis gel blots.
    No preview · Article · Dec 2004 · Journal of Chromatography A
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    ABSTRACT: Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1–8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 µM) or omapatrilat (32 nM) were 38.7 ± 2.4, 51.2 ± 4.7 and 114.7 ± 9.3 min, respectively and BrBK was degraded into BrBK1–8, BrBK1–7, BrBK1–5 and Br-Phe5. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, omapatrilat abolished the production of BrBK1–5 and BrBK1–7, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found. In addition the production of BrBK1–8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or omapatrilat (50 nM) were 9.31 ± 1.7, 22.06 ± 3.1 and 25.3 ± 1.7 min, respectively and BrBK was degraded into BrBK1–8, BrBK1–7, BrBK1–5 and Br-Phe5 plus BrBK2–9, BrBK4–8 and BrBK2–8 metabolites not found in human plasma. GW660511X and omapatrilat reduced the production of BrBK1–5 and BrBK1–7 with more effect being observed with omapatrilat. GW660511X and omapatrilat increased the production of both BrBK1–8 and Br-Phe5 but not that of BrBK4–8 and BrBK2–8. This study shows that the potency of GW660511X in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd.
    No preview · Article · Dec 2002 · Journal of Peptide Science