Temocapril

Temocapril

Promoter Polymorphism of RGS2 Gene Is Associated with Change of Blood Pressure in Subjects with Antihypertensive Treatment: The Azelnidipine and Temocapril in Hypertensive Patients with Type 2 Diabetes Study.[Pubmed:20981351]

Int J Hypertens. 2010 Aug 24;2010:196307.

We performed a prospective study to examine the genetic effect on the response to a calcium (Ca) channel blocker, azelnidipine and an ACE inhibitor, Temocapril treatment in patients with hypertension, as a part of the prior clinical trial, the Azelnidipine and Temocapril in Hypertensive Patients with Type 2 Diabetes Study (ATTEST). Methods and Results. All subjects who gave informed consent for genetic research were divided into two groups: the subjects treated with azelnidipine or Temocapril, for 52 weeks. We selected 18 susceptible genes for hypertension and determined their genotypes using TaqMan PCR method. RNA samples were extracted from peripheral blood, and quantitative real time PCR for all genes was performed using TaqMan method. One of the polymorphisms of the RGS2 gene was extracted as being able to influence the effect of these treatments to reduce BP. At eight weeks, BP change showed a significant interaction between the A-638G polymorphism of Regulator of G protein signaling-2 (RGS2) gene and treatment with azelnidipine or Temocapril. There was no gene whose expression was associated with BP phenotypes or the polymorphisms of each gene. Conclusions. A-638G polymorphism of the RGS-2 gene could be a predictive factor for therapeutic performance of Ca channel blockers.

Prediction of human intestinal absorption of the prodrug temocapril by in situ single-pass perfusion using rat intestine with modified hydrolase activity.[Pubmed:21474683]

Drug Metab Dispos. 2011 Jul;39(7):1263-9.

Intestinal absorption of Temocapril, a prodrug of Temocaprilat, was evaluated in an in situ rat jejunal perfusion model under various conditions of luminal pH and in the presence and absence of carboxylesterase-mediated hydrolysis. Temocapril was more easily taken up by mucosal cells at a luminal pH of 5.4 than at pH 6.4 or 7.4 and was extensively hydrolyzed to Temocaprilat in mucosal cells. The hydrolysis was limited by the intrinsic clearance and the influx rate at luminal perfusate pHs of 5.4 and 7.4, respectively. Temocaprilat, derived from Temocapril, was transported into both mesenteric vein and jejunal lumen according to pH partition theory. The net absorption of both Temocapril and Temocaprilat was highest at a luminal perfusate pH of 5.4. When both the luminal and venous fluid were at pH 7.4, Temocaprilat was transported approximately 3-fold faster into the lumen than into the vein, due presumably to the greater surface area of the brush border membrane because of the presence of microvilli. Under carboxylesterase-inhibited conditions, the hydrolysis of Temocapril was inhibited by only 50%. It is postulated that serine esterases located on the membranes of the epithelial cells were responsible for the residual hydrolysis. We have confirmed that Temocapril is most easily absorbed in the proximal intestine after meals, due to prolongation of the gastric emptying time, the lower intraluminal pH caused by secretion of bile acid, and the interaction between serine esterases and the digesta.

Matrix metalloproteinase-2 inhibition by temocapril and its important role in peritoneal transport.[Pubmed:23013132]

Clin Exp Pharmacol Physiol. 2012 Oct;39(10):864-8.

1. Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodelling during peritoneal injury caused by peritoneal dialysis (PD), but MMP-2 inhibitors have not yet been used clinically. Recently, it was reported that captopril, an angiotensin-converting enzyme inhibitor (ACEI), can inhibit MMP-2. 2. To investigate the potential usefulness of ACEI during PD, the molecular interaction between the MMP-2 active site and the active form of Temocapril (Temocaprilat) was investigated using molecular modelling. Furthermore, the effects of Temocapril on MMP-2 activity in peritoneal effluents and the peritoneal solute transport rate of PD patients were determined. 3. Temocaprilat bound to the MMP-2 active centre and recognized two hydrophobic substrate-binding sites in the MMP-2 molecular model. Matrix metalloproteinase-2 activity in peritoneal effluents was directly inhibited by Temocaprilat (IC(50) 0.47 mumol/L). In one patient given Temocapril, the peritoneal solute transport rate decreased gradually during PD. 4. Temocapril may prove to be an important candidate for development as a novel therapeutic agent for MMP-2 inhibition to prevent peritoneal injury caused by PD.

Evaluation of transport mechanism of prodrugs and parent drugs formed by intracellular metabolism in Caco-2 cells with modified carboxylesterase activity: temocapril as a model case.[Pubmed:21618543]

J Pharm Sci. 2011 Sep;100(9):3985-94.

The intestinal absorption mechanism of Temocapril, an ester-type prodrug of Temocaprilat, was evaluated using Caco-2 cell monolayers with or without active carboxylesterase (CES)-mediated hydrolysis. The inhibition of CES-mediated hydrolysis was achieved by pretreatment of the monolayers with bis-p-nitrophenyl phosphate (BNPP), which inhibited 94% of the total hydrolysis of Temocapril in the Caco-2 cells. The remaining 6% hydrolysis was due to the presence of serine esterases, other than CES, on the cell membranes. Transport experiments under CES-inhibited conditions showed Temocapril not to be a substrate for peptide transporter 1 (PEPT1) or organic anion transporting polypeptides (OATPs), but to be an inhibitor of PEPT1; P-glycoprotein (P-gp) and breast-cancer-resistant protein (BCRP) were responsible for the efflux of Temocapril, which was mainly absorbed by passive diffusion at low apical pH. In Caco-2 cell monolayers with CES-mediated hydrolysis intact, Temocaprilat derived from Temocapril, was 2.5-fold more rapidly transported into the apical compartment than into the basolateral compartment due to the presence of microvilli on the apical membrane. In contrast, Temocaprilat at low intracellular concentrations, was preferentially transported across the basolateral membrane under CES-inhibited conditions.