Lack of Interaction Between the Peptidomimetic Substrates Captopril and Cephradine

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97250/1/0091270008329554.pd

Oral absorption of ACE inhibitors.

In order to elucidate the mechanism and structural requirement for transport via the intestinal peptide carrier system, the transport characteristics of the angiotensin-converting enzyme inhibitor (ACE-I) enalapril, and three other new ACE-I's, quinapril, benazepril, and CGS 16617 were investigated using brush border membrane vesicles from the rabbit jejunum and an in situ single pass perfusion of rat jejunum, respectively. In addition, since captopril (an ACE-I) and cephradine (an oral antibiotic) have been shown to be absorbed by the same peptide transport pathway, the significance of the potential drug interaction between these two drugs was investigated in healthy subjects. In vitro analysis of (\sp{14}C) -enalapril uptake using a rapid filtration technique demonstrated trans stimulation by cephradine and cefadroxil and trans inhibition by lisinopril and enalapril. The results of trans stimulation of enalapril uptake by cephradine and cefadroxil further supports the suggestion that ACE inhibitors are transported in part by the peptide carrier across the transepithelial membrane. Enalaprilat acted as a competitive inhibitor of enalapril by binding at the substrate site without undergoing transport. Cephradine, enalaprilat, lisinopril and quinapril competitively inhibited the transport of enalapril in zero trans experiments with K\sb{\rm i} values of 4.79 mM, 5.76 mM, 0.11 mM, and 0.89 mM, respectively. The prodrugs quinapril and benazepril were well absorbed with parallel saturable and passive mechanisms. In contrast, their respective active diacids, quinaprilat and benazeprilat were poorly absorbed. Both saturable absorption and competitive inhibition by peptide absorption inhibitors indicated that quinapril and benazepril are transported via the peptide pathway. The diacid CGS 16617 has a low permeability, and its transport mechanism could not be elucidated using this technique. The oral bioavailability of several of the prodrug ACE inhibitors may be limited by pre-absorptive gut metabolism and post-absorptive biliary excretion. The pharmacokinetics of captopril was determined in an open, randomized three-way crossover design. Nine healthy subjects were given either an oral dose of captopril (25 mg) or cephradine (500 mg) or their combination. Although the mean AUC and C\sb{\rm max} were lower with a longer T\sb{\rm max}, following oral coadministration of captopril and cephradine, these differences in parameter estimates were not statistically significant.Ph.D.Health and Environmental SciencesPharmaceutical sciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128958/2/9303843.pd

Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits

Retinal and choroidal vascular diseases, with their associated abnormalities in vascular permeability, account for the majority of patients with vision loss in industrialized nations. VEGF is upregulated in ischemic retinopathies such as diabetes and is known to dramatically alter vascular permeability in a number of nonocular tissues via Src kinase–regulated signaling pathways. VEGF antagonists are currently in clinical use for treating the new blood vessels and retinal edema associated with neovascular eye diseases, but such therapies require repeated intraocular injections. We have found that vascular leakage following intravitreal administration of VEGF in mice was abolished by systemic or topical delivery of what we believe is a novel VEGFR2/Src kinase inhibitor; this was confirmed in rabbits. The relevance of Src inhibition to VEGF-associated alterations in vascular permeability was further substantiated by genetic studies in which VEGF injection or laser-induced vascular permeability failed to augment retinal vascular permeability in Src–/– and Yes–/– mice (Src and Yes are ubiquitously expressed Src kinase family members; Src–/– and Yes–/– mice lacking expression of these kinases show no vascular leak in response to VEGF). These findings establish a role for Src kinase in VEGF-mediated retinal vascular permeability and establish a potentially safe and painless topically applied therapeutic option for treating vision loss due to neovascular-associated retinal edema