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.

A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of dual ACE/NEP inhibitor GW660511X in mild-to-moderate hypertensive patients

“…Accumulation of bradykinin or one of its metabolites (BK1-8) is believed to be involved in the occurrence of angioedema, 25,26 and omapatrilat protects bradykinin from degradation and increases the production of BK1-8 by two-to threefold over GW660511X. 27 Consequently, the risk of angioedema may be less for GW660511X than for omapatrilat. However, studies of longer duration, in larger populations and in different ethnic groups are needed to further clarify the safety of GW660511X.…”

The application of inductively coupled plasma mass spectrometry in pharmaceutical and biomedical analysis

“…A similar simultaneous detection approach was utilized on bradykinin metabolism in human and rat plasma [43,44]. In these studies, the bradykinin was bromine-labelled to enable detection and quantification by ICP-MS. A further enhancement of this approach was afforded by Axelsson et al [45] who combined ICP-MS with accurate mass measurement of their organic pharmaceutical compounds.…”

Liquid chromatography coupled with inductively coupled plasma mass spectrometry in the pharmaceutical industry: selected examples

“…We utilised a new analytical method [12,13] that combines LC on-line with ICP-MS and oa-TOF-MS to investigate the metabolism of brominated substance P (BrSubP) in incubations containing human plasma. The substance P substrate utilised was brominated on the phenylalanine (para position) at position 8, i.e.…”

“…A similar simultaneous detection approach was utilised for our studies on bradykinin metabolism in human and rat plasma [12,13]. In these studies, the bradykinin was bromine-labelled to enable detection and quantification by ICP-MS. A further enhancement of this approach was afforded by Axelsson et al [14] who combined ICP-MS with accurate mass measurement of their organic pharmaceutical compounds.…”