enalaprilat-anhydrous and quinaprilat

The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers.. In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h.. The area under the plasma concentration-time curve from 0 h to infinity (AUC0-∞) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC0-∞ ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril.. The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Carboxylic Ester Hydrolases; Cross-Over Studies; Enalapril; Enalaprilat; Female; Genotype; Healthy Volunteers; Heart Rate; Humans; Male; Polymorphism, Single Nucleotide; Quinapril; Tetrahydroisoquinolines; Young Adult

The aim of the present study was to assess the possible differences in hemodynamic and neurohumoral responses to local ACE inhibition in the human forearm of patients with essential hypertension with either quinaprilat or enalaprilat. Forearm vascular responses to infusion of quinaprilat or enalaprilat (0.5 microg/dL/min) into the brachial artery were studied in 12 male patients with essential hypertension. The experiments were performed in a randomized, double-blind, crossover fashion. Before and during ACE inhibition, the vasoconstrictor response to four cumulative doses of angiotensin I (Ang I) was studied. Forearm blood flow was assessed using venous occlusion plethysmography. Local quinaprilat infusion induced a more rapid (even after 15 minutes; median vasodilation quinaprilat 29% vs. enalaprilat --1%, P < 0.02) and longer lasting forearm vasodilation as compared with enalaprilat. After 15 minutes of local ACE inhibition, the vasoconstrictor response to Ang I was completely blocked by both ACE inhibitors. We conclude that in patients with essential hypertension quinaprilat induces a more rapid and longer lasting vasodilatation than enalaprilat. These effects of quinaprilat are possibly related to its higher affinity for vascular ACE. On the other hand, the fact that these effects of quinaprilat were observed despite a similar degree of ACE inhibition as during enalaprilat may suggest that quinaprilat directly stimulates another vasodilatating mechanism.

Topics: Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Enalaprilat; Forearm; Heart Rate; Humans; Hypertension; Isoquinolines; Male; Middle Aged; Peptidyl-Dipeptidase A; Regional Blood Flow; Tetrahydroisoquinolines; Vasodilation

Angiotensin-converting enzyme (ACE) inhibitors differ in their ability to inhibit tissue ACE. This study was, therefore, undertaken to determine whether high tissue affinity ACE inhibitors would improve endothelial function and thereby decrease tissue necrosis during ischemia.. In a porcine model, the second and third diagonal vessels were occluded for 90 minutes, followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion. During the period of coronary occlusion, 10 pigs received enalaprilat (low affinity tissue ACE inhibitor), 0.05 mg/kg intravenously, 10 received quinaprilat (high affinity tissue ACE inhibitor), 10 mg intravenously, and 10 others received no ACE inhibitor.. Wall motion scores (4, normal, to -1, dyskinesia) were higher in animals treated with ACE inhibitors (3.20+/-0.15 SE enalaprilat versus 3.08+/-0.23 quinaprilat versus 1.52+/-0.07 no ACE; both p < 0.0001 from no ACE). Endothelial-dependent relaxation to bradykinin was best preserved in the quinaprilat-treated hearts (32.1%+/-7.6% enalaprilat versus 65.8%+/-12.6% quinaprilat versus 30.6%+/-10.7% no ACE; p < 0.0001 from no ACE; p < 0.005 from enalaprilat). This was associated with a greater reduction in infarct size: area necrosis/area risk 24.3%+/-0.8% enalaprilat (p < 0.0001 from no ACE) versus 14.3%+/-3.2% quinaprilat (p < 0.0001 from no ACE; p < 0.005 from enalaprilat) versus 40.0%+/-1.7% no ACE.. ACE inhibitors with higher affinity to tissue ACE result in better preservation of endothelial function and less tissue necrosis during coronary revascularization.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Enalaprilat; Endothelium, Vascular; Infusions, Intravenous; Isoquinolines; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Swine; Tetrahydroisoquinolines

We examined the effects of quinaprilat, an active metabolite of quinapril (an angiotensin converting enzyme (ACE) inhibitor) on the increase in intracellular concentration of Ca2+ ([Ca2+]i) (Ca2+-overload) induced by lysophosphatidylcholine (LPC) in isolated rat cardiomyocytes. LPC (15 microM) produced Ca2+-overload with a change in cell-shape from rod to round. Quinaprilat but not quinapril at 20 or 50 microM attenuated the LPC-induced increase in [Ca2+]i and the change in cell-shape in a concentration-dependent manner. Since quinaprilat has an inhibitory action on ACE and quinapril has practically no inhibitory action on ACE, it is likely that the inhibitory action of quinaprilat on ACE is necessary for the protective effect of the drug against LPC-induced changes. We therefore examined the effects of enalapril (another ACE inhibitor with the weak inhibitory action on ACE) and enalaprilat (an active metabolite of enalapril with an inhibitory action on ACE) on the LPC-induced changes. Both enalapril and enalaprilat attenuated the LPC-induced Ca2+-overload, suggesting that the inhibitory action on ACE may not mainly contribute to the protective effect of ACE inhibitors against LPC-induced Ca2+-overload. This suggestion was supported by the fact that neither ACE (0.2 U/ml) nor angiotensin II (0.1-100 microM) increased [Ca2+]i in isolated cardiomyocytes. Furthermore, application of bradykinin (0.01-10 microM) did not enhance the protective effect of quinaprilat against LPC-induced changes. LPC also increased release of creatine kinase (CK) from the myocyte markedly, and quinaprilat but not quinapril attenuated the LPC-induced CK release. Unexpectedly, both enalapril and enalaprilat did not attenuate the LPC-induced CK release. Neither quinapril nor quinaprilat changed the critical micelle concentration of LPC, suggesting that these drugs do not directly bind to LPC. We conclude that quinaprilat attenuates the LPC-induced increase in [Ca2+]i, and that the protective effect of quinaprilat on the LPC-induced change may not be related to a decrease in angiotensin II production or an increase in bradykinin production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Calcium; Cell Size; Creatine Kinase; Enalapril; Enalaprilat; Isoquinolines; Lysophosphatidylcholines; Male; Micelles; Myocardium; Propranolol; Quinapril; Rats; Rats, Sprague-Dawley; Tetrahydroisoquinolines; Vasodilator Agents

The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalaprilat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat. To understand the reasons for such discrepancies between ex vivo effects of ACE inhibitors and in vitro actions of their diacid metabolites, we measured the lipophilicities of the compounds and investigated the possibility that trandolapril could display an ACE inhibitory effect by itself. Trandolaprilat was found to be far more lipophilic than enalaprilat, as shown by reverse-phase high-performance liquid chromatography studies performed at pH 7.4 (log kw7.4 = 1.487 vs. 0.108). In addition, trandolapril was practically as active in vitro as its diacid metabolite (IC50 = 2.5 vs. 1.35 nM) in inhibiting ACE activity in the aorta, whereas enalapril was practically devoid of any effect (IC50 = 240 nM). Measurements of relative affinities of inhibitors or metabolites for purified human renal ACE showed that trandolapril displayed about 20% of the affinity of its diacid metabolite (IC50 = 15 vs. 3.2 nM); enalaprilat affinity (34 nM) was within the same range as those of trandolapril and trandolaprilat, whereas enalapril displayed a very low affinity for the purified enzyme (IC50 = 50 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalapril; Enalaprilat; Indoles; Isoquinolines; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Solubility; Tetrahydroisoquinolines

Angiotensin (Ang) I converting enzyme (ACE) inhibitors represent a major advance in the treatment of congestive heart failure, and tissue, rather than circulating ACE, may be their major site of action. However, assessments of tissue ACE inhibition in treated patients has not always supported this contention. In these studies, ACE activity was measured in homogenates of sampled tissue by biochemical methods. In the present study, using a model system, we have examined the validity of these tissue-sampling methods. Functional ACE activity was determined by comparing positive inotropic responses to [Pro10]Ang I in either vehicle-pretreated or ACE inhibitor-pretreated papillary muscles. [Pro10]Ang I elicits a response, which is entirely dependent on ACE-mediated conversion to Ang II. The ACE inhibitors studied were captopril, enalaprilat, lisinopril, and quinaprilat. In a parallel study, papillary muscle ACE activity was also measured in homogenates using [125I]MK-351A (a radiolabeled ACE inhibitor) binding. The studies indicate that the tissue-sampling method significantly underestimated functional ACE inhibition in hamster papillary muscles (p < 0.001). Kinetic studies indicated that the half-time for the dissociation of [3H]enalaprilat and [3H]lisinopril from hamster ventricular ACE was 4.5 and 6.2 minutes, respectively. The dissociation of [3H]quinaprilat was biphasic (half-time, 47 and 90 minutes), indicating that the two active sites of somatic ACE differ in their ability to bind to this inhibitor. The rapid rate of ACE inhibitor dissociation suggests that, during the time taken to assay ACE activity biochemically, the enzyme becomes "disinhibited," leading to an underestimation of functional ACE inhibition. ACE inhibitor dissociation rates were partially predictive of the duration of functional ACE inhibition in papillary muscles; other factors that appeared to contribute were "tissue trapping" of the inhibitor and de novo synthesis of ACE in papillary muscles. Quantification of tissue ACE inhibition and its relation to drug efficacy must, therefore, involve a careful consideration of these factors to avoid artifacts in clinical decision making and in assessments of pathogenic mechanisms involved in congestive heart failure.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Captopril; Cricetinae; Dipeptides; Enalaprilat; Humans; Isoquinolines; Lisinopril; Male; Mesocricetus; Papillary Muscles; Tetrahydroisoquinolines