title: Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and omapatrilat.
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 (79/81 Br-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 microM) 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-Phe. 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.
authors.affiliation: GlaxoSmithkline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK.
authors.forename: Olivier
authors.initials: O
authors.lastname: Heudi
authors.forename: Cesar
authors.initials: C
authors.lastname: Ramirez-Molina
authors.forename: Peter
authors.initials: P
authors.lastname: Marshall
authors.forename: Augustin
authors.initials: A
authors.lastname: Amour
authors.forename: Simon
authors.initials: S
authors.lastname: Peace
authors.forename: Stephen
authors.initials: S
authors.lastname: McKeown
authors.forename: Fadi
authors.initials: F
authors.lastname: Abou-Shakra
mesh_terms: D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000097:blood* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D015260:Neprilysin / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013841:Thiazepines / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C475484:GW660511X; D011725:Pyridines; D013841:Thiazepines; D013844:Thiazoles; C106266:omapatrilat; D015260:Neprilysin; D001920:Bradykinin