Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

BACKGROUND: The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class. METHODS: The model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4°C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest. RESULTS: The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution. CONCLUSION: If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained

The cardiac renin-angiotensin system in heart failure

The success of angiotensin-converting enzyme (ACE) inhibitors in reducing cardiovascular morbidity and mortality rates has led to a reexamination of the role of the renin-angiotensin system in pathophysiology. Ventricular dysfunction leading to congestive cardiac failure is associated with sequential activation of the sympathetic system and increases in plasma atrial natriuretic peptide; however, increases in plasma renin and aldosterone do not occur until very late. The renin-angiotensin system is now regarded as both a circulating and tissue hormonal system. All components of the renin-angiotensin system have been detected in the heart. ACE is localized in discrete areas of the heart, including the cardiac valves, coronary vessels, atria, and myocardium. After experimental myocardial infarction in the rat, although plasma renin and aldosterone levels are not increased, ACE in the myocardium is markedly increased. Treatment with ACE inhibitors suppresses cardiac ACE and is associated with hemodynamic improvement, reversal of the neurohumoral activation, prevention of ventricular dilatation, and remodeling and reduction in mortality rates. These results suggest that the beneficial effects of ACE inhibitors in treating congestive cardiac failure, preventing ventricular remodeling, and regressing left ventricular hypertrophy may involve not only reducing preload and afterload but also suppressing the local cardiac renin-angiotensin system

Inhibition of angiotensin converting enzyme (ACE) in plasma and tissue

Inhibition of angiotensin-converting enzyme (ACE) in rat plasma and tissue was studied after administration of quinapril, a new orally active ACE inhibitor with an intermediate duration of action. Tissue and plasma ACE was assessed by a radioinhibitor-binding assay and by in vitro autoradiography using [125I]351A as the radioligand. Individual tissues in rats were differentially inhibited in time and degree. The highest ACE inhibition in plasma and in tissues occurred within the first 2 h after gavage treatment with quinapril, 0.3 mg/kg. After 24 h, ACE was still inhibited by 25% in plasma, by 30% in the aorta, by 35% in the kidneys, and by more than 40% in cardiac atria and ventricles. Plasma and kidney tissues showed increasing ACE inhibition in a dose-dependent manner after oral dosing with quinapril. In the brain, only the structures outside the blood-brain barrier were inhibited after the administration of 0.1 mg/kg of quinapril. Similarly, testicular ACE was unaffected by quinapril. These results demonstrate a prolonged effect of quinapril on tissue ACE and suggest that ACE inhibition in the heart, vasculature, and kidneys may be of particular importance in pathologic states such as hypertension or heart failure

Inhibition of angiotensin converting enzyme (ACE) in plasma and tissues: studies ex vivo after administration of ACE inhibitors

Two methods of radio-inhibitor binding to tissue membrane homogenates and in vitro autoradiography have been used for ex vivo studies on the inhibition of tissue angiotensin converting enzyme (ACE) following acute and chronic administration of ACE inhibitors. Tissue ACE is differentially inhibited in time and degree in different tissues of the rat. Plasma and kidney ACE are inhibited completely at low doses whereas lung and aorta are only inhibited by 60-70%, even after very high does of ACE inhibitors. In the brain only those structures outside the blood-brain barrier are inhibited at low doses but at high doses perindopril appears able to cross the blood-brain barrier. Similarly, testicular ACE is not inhibited and appears to be protected by a blood-testis barrier. Preliminary results suggest that after chronic administration there is also a variable pattern of induction and inhibition of ACE in different tissues. By relating the degree of tissue inhibition to physiological responses it may be possible to determine the role of local renin-angiotensin systems in regional haemodynamics and in the hypotensive action of ACE inhibitors. Further, the techniques of radioligand inhibitor binding and in vitro autoradiography can be extended to other important cardiovascular enzymes (renin and kallikrein) when suitable high affinity specific inhibitors become available

Characterization of cardiac angiotensin converting enzyme (ACE) and in vivo inhibition following oral quinapril to rats

1. Angiotensin converting enzyme (ACE) from the rat heart and lung was studied by use of the radioligand [125I]-351A. 2. Displacement of the bound radioinhibitor [125I]-351A was used to assess the relative potency of six ACE inhibitors in rat heart and lung homogenates and estimate the binding association constant (KA). 3. The KA for atrial preparations was significantly higher than that of the lung (P less than 0.025) and also the ventricles (P less than 0.005). Ventricular preparations and preparations from the lung also differed significantly (P less than 0.05). These differences in KA were noted for all six ACE inhibitors used to displace the radioligand. 4. The rank order of potency of the ACE inhibitors was quinaprilat = benazeprilat greater than perindoprilat greater than 351A greater than lisinopril greater than fosinoprilat. 5. Cardiac ACE inhibition was studied ex vivo following oral administration of quinapril to rats. Following 0.3 mg kg-1 quinapril, the time course and degree of inhibition of ventricular and atrial ACE were similar. 6. These results suggest that the detected differences in KA noted have only a limited potential biological significance. The difference in KA may reflect variations in the structure or conformation of ACE in different tissues

Comparative studies of tissue inhibition by angiotensin converting enzyme inhibitors

There is increasing evidence that inhibition of tissue angiotensin converting enzyme (ACE) is important for the pharmacokinetics and pharmacodynamic effects of ACE inhibitors. Radioligand inhibitor binding methods using 125I-351A and either tissue homogenates or in vitro autoradiography have allowed in vitro and ex vivo quantitation of tissue ACE inhibition by a variety of ACE inhibitors. The rank order of potency against plasma as well as lung, kidney, and cardiac homogenates was quinaprilat = benazeprilat greater than perindoprilat greater than lisinopril greater than enalaprilat greater than fosinoprilat. The highest concentration of ACE in the heart was found in the cardiac valves followed by the right and left atria, then the right and left ventricles. Ex vivo studies showed that after oral administration of quinapril, ACE was inhibited dose-dependently in the lung, kidney, aorta and heart for more than 24h. Tissue bioavailability of the inhibitor is also an important determinant of tissue ACE inhibition. Perindopril crossed the blood-brain barrier and inhibited brain ACE at high doses, but after equivalent doses of quinapril no brain ACE inhibition could be demonstrated. These results suggest that it may be possible to design ACE inhibitors to have specific effects on ACE in different tissues

Interaction between atrial natriuretic peptide and the renin angiotensin aldosterone system. Endogenous antagonists

The biologic actions of the cardiac peptide hormone atrial natriuretic peptide (ANP) of vasorelaxation, diuresis and natriuresis, suppression of aldosterone, vasopressin release, and thirst are the opposite of those of the renin angiotensin system. This close relationship is further strengthened by the complementary localization of their receptors in the brain, adrenal gland, vasculature, and kidney. In many physiologic situations including postural changes, volume expansion, water immersion, high altitude, and lower body negative pressure, the plasma levels of ANP and angiotensin II change inversely. In congestive heart failure, renin and aldosterone levels may initially be suppressed by high levels of ANP. Similarly the low renin levels associated with increasing age and with elderly hypertensive patients, may be the result of the elevation of plasma ANP that occurs with aging. ANP may thus be the endogenous antagonist of the renin angiotensin aldosterone system. These two opposing systems allow fine-tuning of volume and pressure by the body

High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage

BACKGROUND: Angiotensin II (AngII) contributes to salt-driven kidney damage. In this study, we aimed at investigating whether and how the renal damage associated with a high-salt diet could result from changes in the ratio between angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). METHODS: Forty-eight rats randomly allocated to three different dietary contents of salt were studied for 4 weeks after undergoing a left uninephrectomy. We focussed on kidney functional, structural and molecular changes. At the same time, we studied kidney molecular changes in 20 weeks old Ace2-knockout mice (Ace2KO), with and without ACE inhibition. RESULTS: A high salt content diet significantly increased the glomerular ACE/ACE2 ratio. This was associated with increased oxidative stress. To assess whether these events were related, we measured renal oxidative stress in Ace2KO, and found that the absence of ACE2 promoted oxidative stress, which could be prevented by ACE inhibition. CONCLUSION: One of the mechanisms by which a high-salt diet leads to renal damage seems to be the modulation of the ACE/ACE2 ratio which in turn is critical for the cause of oxidative stress, through AngII