temocapril-hydrochloride and temocaprilat

Recent reports have shown that genetic polymorphisms in organic anion transporting polypeptide (OATP) 1B1 have an effect on the pharmacokinetics of drugs. However, the impact of OATP1B1*1b alleles, the frequency of which is high in all ethnicities, on the pharmacokinetics of substrate drugs is not known after complete separation of subjects with OATP1B1*1a and *1b. Furthermore, the correlation between the clearances of OATP1B1 substrate drugs in individuals has not been characterized. We investigated the effect of genetic polymorphism of OATP1B1, particularly the *1b allele, on the pharmacokinetics of 3 anionic drugs, pravastatin, valsartan, and temocapril, in Japanese subjects.. Twenty-three healthy Japanese volunteers were enrolled in a 3-period crossover study. In each period, after a single oral administration of pravastatin, valsartan, or temocapril, plasma and urine were collected for up to 24 hours.. The area under the plasma concentration-time curve (AUC) of pravastatin in *1b/*1b carriers (47.4 +/- 19.9 ng.h/mL) was 65% of that in *1a/*1a carriers (73.2 +/- 23.5 ng.h/mL) (P = .049). Carriers of *1b/*15 (38.2 +/- 15.9 ng.h/mL) exhibited a 45% lower AUC than *1a/*15 carriers (69.2 +/- 23.4 ng.h/mL) (P = .024). In the case of valsartan we observed a similar trend as with pravastatin, although the difference was not statistically significant (9.01 +/- 3.33 microg.h/mL for *1b/*1b carriers versus 12.3 +/- 4.6 microg.h/mL for *1a/*1a carriers [P = .171] and 6.31 +/- 3.64 microg.h/mL for *1b/*15 carriers versus 9.40 +/- 4.34 microg.h/mL for *1a/*15 carriers [P = .213]). The AUC of temocapril also showed a similar trend (12.4 +/- 4.1 ng.h/mL for *1b/*1b carriers versus 18.5 +/- 7.7 ng.h/mL for *1a/*1a carriers [P = .061] and 16.4 +/- 5.0 ng.h/mL for *1b/*15 carriers versus 19.0 +/- 4.1 ng.h/mL for *1a/*15 carriers [P = .425]), whereas that of temocaprilat (active form of temocapril) was not significantly affected by the haplotype of OATP1B1. Interestingly, the AUC of valsartan and temocapril in each subject was significantly correlated with that of pravastatin (R = 0.630 and 0.602, P < .01). The renal clearance remained unchanged for each haplotype for all drugs.. The major clearance mechanism of pravastatin, valsartan, and temocapril appears to be similar, and OATP1B1*1b is one of the determinant factors governing the interindividual variability in the pharmacokinetics of pravastatin and, possibly, valsartan and temocapril.

Topics: Adult; Animals; Antihypertensive Agents; Area Under Curve; Cells, Cultured; Cross-Over Studies; Dogs; Haplotypes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Male; Metabolic Clearance Rate; Organic Anion Transporters; Polymorphism, Genetic; Pravastatin; Tetrazoles; Thiazepines; Valine; Valsartan

The aim of this study was to determine the potential impact of age on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat, in hypertensive patients.. Male and female patients with mild to moderate essential hypertension (DBP 95-114 mmHg inclusive) were allocated to two age groups: young, < or = 40 years; elderly, > or = 69 years, (n = 18 per group). In Part I of the study, subjects took a single oral tablet dose of 20 mg temocapril hydrochloride following an overnight fast. In Part II they took seven once daily oral tablet doses of 20 mg temocapril hydrochloride. Pharmacokinetic profiles were determined after the single and the last dose. Trough plasma samples were taken before each dose in Part II. Urine was collected for 24 h following the single and the last dose.. Steady state was reached within 1 week in both groups. Statistically significant differences were detected in AUC and AUCss for temocaprilat as well as in CL(R) for temocapril and temocaprilat, respectively, after a single dose and at steady state. All other pharmacokinetic parameters for temocapril and temocaprilat did not show any significant difference.. The pharmacokinetic differences detected in the elderly do not require a dose adjustment per se. Nonetheless, a lower starting dose may be appropriate as elderly hypertensive patients are usually considered to be at an increased risk of first dose hypotension at the onset of treatment with an ACE inhibitor.

Topics: Adult; Age Factors; Aged; Antihypertensive Agents; Female; Humans; Hypertension; Male; Middle Aged; Thiazepines

The aim of this study was to determine the potential influence of renal impairment on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat.. Non-compartmental pharmacokinetics were assessed in four groups of hypertensive patients (n=8 per group, four investigational centres) with normal (creatinine clearance determined via 24 h urine sampling, CL[CR], > or = 60 ml min-1) and impaired renal function (CL[CR] 40-59, 20-39, < 20 ml min-1) after 14 once daily oral doses of 10 mg temocapril hydrochloride.. For temocapril, there were no statistically significant differences in median tmax or mean Cmax, AUC(SS), t1/2,Z, CL/F between the four groups. Renal clearance, CL(R), for temocapril showed a linear decreasing trend with decreasing CL(CR) [mean (s.d.): 32.2 (10.7) to 3.7 (3.0) ml min-1]. Steady-state for temocaprilat was reached on day 5. For temocaprilat, no statistically significant differences in mean Cmax or median tma were detected. With decreasing mean CL(CR), mean AUC(SS) for temocaprilat increased statistically significantly although only 2.4-fold [mean (s.d.): 2115 (565) to 4989 (2338) ng ml-1 h] and t1/2,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CL(R) for temocaprilat showed a linear decreasing trend with decreasing CL(CR) [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min-1].. These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat. This may be attributed to the dual, i.e. renal and biliary, elimination pathway of the drug.

Topics: Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Area Under Curve; Creatinine; Female; Humans; Kidney Diseases; Male; Middle Aged; Thiazepines

Temocapril is a prodrug whose hydrolysis by carboxylesterase 1 (CES1) yields the active ACE inhibitor temocaprilat. This molecular-dynamics (MD) study uses a resolved structure of the human CES1 (hCES1) to investigate some mechanistic details of temocapril hydrolysis. The ionization constants of temocapril (pK1 and pK3) and temocaprilat (pK1, pK2, and pK3) were determined experimentally and computationally using commercial algorithms. The constants so obtained were in good agreement and revealed that temocapril exists mainly in three ionic forms (a cation, a zwitterion, and an anion), whereas temocaprilat exists in four major ionic forms (a cation, a zwitterion, an anion, and a dianion). All these ionic forms were used as ligands in 5-ns MS simulations. While the cationic and zwitterionic forms of temocapril were involved in an ion-pair bond with Glu255 suggestive of an inhibitor behavior, the anionic form remained in a productive interaction with the catalytic center. As for temocaprilat, its cation appeared trapped by Glu255, while its zwitterion and anion made a slow departure from the catalytic site and a partial egress from the protein. Only its dianion was effectively removed from the catalytic site and attracted to the protein surface by Lys residues. A detailed mechanism of product egress emerges from the simulations.

Topics: Algorithms; Angiotensin-Converting Enzyme Inhibitors; Biotransformation; Carboxylesterase; Computer Simulation; Electrochemistry; Ligands; Models, Biological; Models, Molecular; Potentiometry; Software; Thiazepines; X-Ray Diffraction

Background- We have recently identified that endothelium-derived hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans, for which endothelial nitric oxide synthase (eNOS) is an important source. Angiotensin-converting enzyme (ACE) inhibitors are known to enhance EDHF-mediated responses. In this study, we examined whether endothelium-derived H2O2 accounts for the enhancing effect of an ACE inhibitor on EDHF-mediated responses and, if so, what mechanism is involved.. Control and eNOS-/- mice were maintained with or without temocapril (10 mg/kg per day orally) for 4 weeks, and isometric tensions and membrane potentials of mesenteric arteries were recorded. In control mice, temocapril treatment significantly enhanced EDHF-mediated relaxations and hyperpolarizations to acetylcholine (n=8 each). Catalase, a specific scavenger of H2O2, abolished the beneficial effects of temocapril, although it did not affect endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of K(Ca) channels (n=6 each). Western blot analysis demonstrated that the temocapril treatment significantly upregulated the expression of eNOS. By contrast, this enhancing effect of temocapril was absent in eNOS-/- mice (n=6).. These results indicate that endothelium-derived H2O2 accounts for the enhancing effect of temocapril on EDHF-mediated responses caused in part by eNOS upregulation, further supporting our H2O2 theory.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Factors; Blood Pressure; Body Weight; Catalase; Endothelium, Vascular; Estradiol; Female; Glutathione; Hydrogen Peroxide; In Vitro Techniques; Isometric Contraction; Membrane Potentials; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Superoxide Dismutase; Thiazepines; Vasodilation

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) have potent antioxidant effects in addition to antihypertensive effects.. We investigated the ability of ACEIs and ARBs to enhance the superoxide scavenging ability of polymorphonuclear leukocytes (PMNLs) from type 2 diabetic patients (n = 32) and healthy subjects (n = 32). The scavenging ability (U/10(3) cells) of superoxide was measured by electron spin resonance. We used ascorbic acid as a positive control antioxidant and tested captopril, temocapril (an inactive form of ACEI), and temocaprilate (an active form of ACEI) as ACEIs, as well as RNH-6270 as an ARB.. Captopril, temocaprilate, and RNH-6270 showed dose-dependent enhancement in scavenging ability. The scavenging ability with captopril and temocaprilate was greater than with RNH-6270. The changes in scavenging ability induced by all of the drugs in diabetic patients were similar to the changes in healthy subjects. A high-glucose medium (400-800 mg/dL) greatly attenuated the drug-induced enhancement of scavenging ability.. We demonstrated that both ACEIs and ARBs enhance superoxide scavenging by PMNLs from type 2 diabetic patients and that a high-glucose environment markedly attenuates the ability of these drugs to augment superoxide scavenging.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Ascorbic Acid; Blood Glucose; Captopril; Diabetes Mellitus, Type 2; Female; Free Radical Scavengers; Humans; Imidazoles; In Vitro Techniques; Male; Middle Aged; Neutrophils; Superoxide Dismutase; Superoxides; Tetrazoles; Thiazepines

In patients with complete bile duct obstruction, the only pathway for the elimination of cholephilic compounds is through the urine. Although changes in various transporters in the liver and kidney in cholestasis have been elucidated, little is known about how effectively the elimination of these compounds is compensated for by urinary excretion.. In the present study, the urinary excretion of pravastatin and temocapril was studied in bile-duct-ligated rats (BDLR) for 3 days and in Eisai hyperbilirubinemic rats (EHBR). After urinary bladder cannulation, radiolabeled pravastatin and temocapril were injected intravenously. Urine samples were collected every 1 h for 4 h, and the radioactivity was counted.. Urinary excretion of pravastatin was markedly increased in BDLR (85.9% of the dose after 4 h) and moderately increased in EHBR (35.9% of the dose after 4 h) compared with that in control rats (5.5% of the dose after 4 h). Similar but less prominent differences were observed with temocapril after it was administered (50.7%, 38.2%, and 22.0% of the dose after 4 h in BDLR, EHBR, and the controls, respectively).. The absence of biliary excretion of anionic drugs was compensated for by urinary excretion in BDLR and EHBR, and the compensation was more efficient with pravastatin than with temocapril. In patients with complete bile duct obstruction, the only pathway for the elimination of cholephilic compounds is through the urine. Although changes in various transporters in the liver and kidney in cholestasis have been elucidated, little is known about how effectively the elimination of these compounds is compensated for by urinary excretion.

Topics: Animals; Bile Ducts; Cholestasis; Disease Models, Animal; Hyperbilirubinemia; Male; Pravastatin; Rats; Rats, Sprague-Dawley; Thiazepines

A simple and sensitive enzyme immunoassay (EIA) for determination of the active metabolite (RS-5139) of a new angiotensin converting enzyme inhibitor (CS-622) was developed. The N-succinimmidyl ester of RS-5139 was coupled with bovine serum albumin (BSA) and its conjugate was used as an immunogen. Horse radish peroxidase (HRP; EC 1, 11, 1, 7) was used as a labeled enzyme and 3, 3', 5, 5'-tetramethylbenzidine was used as a substrate. The antiserum was used at a final dilution of 1:10000 and sensitivity was 10 pg in plasma and 20pg in urine. CS-622 exhibited cross-reactivity (22.3%), but other ACE inhibitors didn't exhibit cross-reactivity. The plasma levels determined by EIA and GC/MS was good agreement (y = 6.58e-2 + 1.07x, R - 2 = 0.985, n = 52).

Topics: Angiotensin-Converting Enzyme Inhibitors; Antibody Specificity; Cross Reactions; Evaluation Studies as Topic; Gas Chromatography-Mass Spectrometry; Humans; Immunoenzyme Techniques; Prodrugs; Thiazepines