Pharmacokinetic and pharmacodynamic study of imidaprilat, an active metabolite of imidapril, a new angiotensin-converting enzyme inhibitor, in spontaneously hypertensive rats

The pharmacokinetics and pharmacodynamics (PK/PD) of imidaprilat, an active metabolite of imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated. Imidapril was infused subcutaneously for 4 weeks via an osmotic pump implanted under the skin in the back of male spontaneously hypertensive rats (SHRs). Plasma concentration of imidaprilat, systolic blood pressure (SBP), and plasma ACE activity were determined periodically. The plasma concentration of imidaprilat increased in proportion to the infusion rates and was maintained for 4 weeks. The SBP and ACE activity did not decrease in proportion to the infusion rates due to the saturation of the pharmacologic effects, but these actions also were maintained for 4 weeks. The PK/PD of imidaprilat were not influenced by aging of SHRs. The antihypertensive action in subcutaneous infusion of imidapril was as potent as that in oral administration at the same dose, although the maximum plasma concentration of imidaprilat in subcutaneous infusion was one-eightieth times of that in oral administration. The action was also maintained 28 times longer than that in oral administration, indicating that subcutaneous infusion is useful as an administration route. Furthermore, good correlation between plasma imidaprilat concentration and SBP was observed in subcutaneous infusion, indicating that plasma concentration may be a useful marker of pharmacologic action.     

Protection of the cardiovascular system by imidapril,a versatile angiotensin-converting enzyme inhibitor

Imidapril hydrochloride (imidapril) is a long-acting, non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, which has been used clinically in the treatment of hypertension, chronic congestive heart failure (CHF), acute myocardial infarction (AMI), and diabetic nephropathy. It has the unique advantage over other ACE inhibitors in causing a lower incidence of dry cough. After oral administration, imidapril is rapidly converted in the liver to its active metabolite imidaprilat. The plasma levels of imidaprilat gradually increase in proportion to the dose, and decline slowly. The time to reach the maximum plasma concentration (T(max)) is 2.0 h for imidapril and 9.3 h for imidaprilat. The elimination half-lives (t(1/2)) of imidapril and imidaprilat is 1.7 and 14.8 h, respectively. Imidapril and its metabolites are excreted chiefly in the urine. As an ACE inhibitor, imidaprilat is as potent as enalaprilat, an active metabolite of enalapril, and about twice as potent as captopril. In patients with hypertension, blood pressure was still decreased at 24 h after imidapril administration. The antihypertensive effect of imidapril was dose-dependent. The maximal reduction of blood pressure and plasma ACE was achieved with imidapril, 10 mg once daily, and the additional effect was not prominent with higher doses. When administered to patients with AMI, imidapril improved left ventricular ejection fraction and reduced plasma brain natriuretic peptide (BNP) levels. In patients with mild-to-moderate CHF [New York Heart Association (NYHA) functional class II-III], imidapril increased exercise time and physical working capacity and decreased plasma atrial natriuretic peptide (ANP) and BNP levels in a dose-related manner. In patients with diabetic nephropathy, imidapril decreased urinary albumin excretion. Interestingly, imidapril improved asymptomatic dysphagia in patients with a history of stroke. In the same patients it increased serum substance P levels, while the angiotensin II receptor antagonist losartan was ineffective. These studies indicate that imidapril is a versatile ACE inhibitor. In addition to its effectiveness in the treatment of hypertension, CHF, and AMI, imidapril has beneficial effects in the treatment of diabetic nephropathy and asymptomatic dysphagia. Good tissue penetration and inhibition of tissue ACE by imidapril contributes to its effectiveness in preventing cardiovascular complications of hypertension. The major advantages of imidapril are its activity in the treatment of various cardiovascular diseases and lower incidence of cough compared with some of the older ACE inhibitors.     

Imidapril in heart failure.

Angiotensin-converting enzyme (ACE) inhibitors improve the prognosis in mild, moderate and severe heart failure, as well as preventing the onset of heart failure in patients with chronic asymptomatic left-ventricular dysfunction and in those with reduced ejection fraction after myocardial infarction (MI). Imidapril is a long-acting ACE inhibitor that is rapidly converted in the liver to its active metabolite, imidaprilat. Maximum plasma concentrations of imidapril and imidaprilat are achieved after 2 and 5-6 hours, respectively, with corresponding elimination half-lives of 1.1-2.5 and 10-19 hours. Imidapril is used in the treatment of hypertension, chronic heart failure, acute MI and diabetic nephropathy. In patients with mild-to-moderate chronic heart failure, imidapril 10 mg once-daily increased exercise time and physical working capacity, decreased plasma atrial natriuretic peptide and brain natriuretic peptide levels and reduced blood pressure. It also improved left ventricular ejection fraction, being significantly more effective than bisoprolol, in patients with acute MI. Imidapril is well tolerated and preliminary studies suggest it has an advantage over captopril and enalapril in terms of a lower incidence of cough. In conclusion, imidapril is a well-investigated versatile ACE inhibitor for the treatment of a range of cardiovascular diseases.     

Imidapril: a review of its use in essential hypertension, Type 1 diabetic nephropathy and chronic heart failure

Imidapril (Tanatril), through its active metabolite imidaprilat, acts as an ACE inhibitor to suppress the conversion of angiotensin I to angiotensin II and thereby reduce total peripheral resistance and systemic blood pressure (BP).In clinical trials, oral imidapril was an effective antihypertensive agent in the treatment of mild to moderate essential hypertension. Some evidence suggests that imidapril also improves exercise capacity in patients with chronic heart failure (CHF) and reduces urinary albumin excretion rate in patients with type 1 diabetes mellitus. Imidapril was well tolerated, with a lower incidence of dry cough than enalapril or benazepril, and is a first choice ACE inhibitor for the treatment of mild to moderate essential hypertension.     

Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with impaired liver function

Objective: The possible influence of impaired liver function on the pharmacokinetic disposition of imidapril, a novel prodrug type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite, imidaprilat, was investigated. Methods: Eight subjects with normal liver function and eight patients with liver dysfunction received an oral dose of 10 mg imidapril once daily for 7 days. Results: Plasma imidapril concentrations after single and, although less pronounced, after repeated dosing were higher in the liver disease patients, whereas imidaprilat concentrations were lower. This suggests that the conversion of imidapril into imidaprilat in the liver is delayed in patients with impaired liver function. However, the slower biotransformation did not result in statistically significant differences in C_max and AUC for either imidapril or its active metabolite following repeated administration. Moreover, no relevant accumulation of either imidapril or imidaprilat occurred after repeated dosing. Conclusions: Imidapril is regarded as an ACE inhibitor of which the pharmacokinetic disposition is only slightly affected in patients with impaired liver function.     

Clearance of imidapril, an Angiotensin-converting enzyme inhibitor, during hemodialysis in hypertensive renal failure patients: comparison with quinapril and enalapril

The dialyzability of imidaprilat, an active metabolite of the angiotensin-converting enzyme (ACE) inhibitor imidapril, was determined and compared with those of enalaprilat and quinaprilat in hypertensive patients on chronic hemodialysis. Imidapril (5 mg/d, n = 6), enalapril (2.5 mg/d, n = 6), or quinapril (2.5 mg/d, n = 6) was given for at least 8 weeks prior to the trial. During dialysis, enalaprilat, but not imidaprilat or quinaprilat, concentrations in both sides decreased significantly. Compared to enalaprilat, the dialyzabilities of imidaprilat and quinaprilat were significantly lower (dialyzer clearance [mL/min/m(2)]: enalaprilat, 41.8 +/- 7.4; imidaprilat, 19.0 +/- 7.8; quinaprilat, 8.9 +/- 1.3). The dialyzabilities of the 3 drugs were negatively correlated with their respective protein-binding rates. During hemodialysis, blood pressure did not change significantly in any group. These results suggest that imidapril provides good blood pressure control without a large fluctuation of drug concentration in hypertensive patients undergoing chronic hemodialysis.     

Imidapril, an angiotensin-converting enzyme inhibitor, inhibits thrombosis via reduction in aortic plasminogen activator inhibitor type-1 levels in spontaneously hypertensive rats.

It is known that angiotensin II (Ang II) exerts an antifibrinolytic effect by stimulating synthesis of plasminogen activator inhibitor type-1 (PAI-1), a specific inhibitor of tissue plasminogen activator (t-PA). The aim of this study was to compare the antithrombotic potency of imidapril, an angiotensin-converting enzyme (ACE) inhibitor, and candesartan, an angiotensin II type 1 (AT1) receptor antagonist, in a model of arterial thrombosis in spontaneously hypertensive rats (SHRs). Oral treatment with 5 mg/kg imidapril 1 h before induction of thrombosis resulted in a significant reduction in thrombus weight, whereas candesartan did not affect thrombus weight under the same treatment conditions. Candesartan lowered blood pressure to the same degree as in the imidapril-treated rats. Imidapril not only reduce the serum and aortic ACE activities, but also reduced aortic PAI-1 protein levels, while candesartan had no effect on theses. These results suggest that imidapril, but not the AT1 receptor antagonist, candesartan, enhances fibrinolysis via a reduction of aortic PAI-1 levels by inhibiting ACE and prevents thrombus formation in SHRs.     

Studies on the Magnitude and the Mechanism of Cough Potentiation by Angiotensin-Converting Enzyme Inhibitors in Guinea-pigs: Involvement of Bradykinin in the Potentiation

One adverse effect of the angiotensin-converting enzyme (ACE) inhibitors used for treatment of hypertension and congestive heart failure is the production of dry coughs. Imidapril is a new type of ACE inhibitor with a very low incidence of coughs. The magnitude and the mechanism of cough potentiation of imidapril and other ACE inhibitors has been studied in guinea-pigs. In normal guinea-pigs single and repeated dosing of imidapril at 0.1 to 100 mg kg^?1 had no effect on capsaicin- or citric acid-induced coughs. Single and repeated dosing of enalapril and captopril at 10 to 30 mg kg^?1, respectively, significantly increased the number of capsaicin-induced coughs. Repeated dosing of 1 mg kg^?1 enalapril also significantly augmented the capsaicin cough. In bronchitic guinea-pigs imidapril also had no effect on the coughs induced by the two stimulants. Enalapril and captopril significantly increased the number of coughs induced not only by capsaicin but also by citric acid. Lower doses of enalapril were enough to augment the capsaicin-induced coughs, whereas medium to large doses failed to augment the cough irrespective of the protocol of administration. Bradykinin-induced discharges of the vagal afferents from the lower airway were significantly increased by enalaprilat but not by imidaprilat. Capsaicin-induced discharges of the afferents were, on the other hand, significantly depressed by enalaprilat, but not by imidaprilat. Interestingly, enalaprilat depression of the discharges was significantly reversed by Hoe-140, a bradykinin B₂ receptor blocker. In guinea-pigs pretreated with a low dose of enalapril, arterial infusion of bradykinin significantly potentiated the coughs induced by capsaicin. The results indicated that imidapril was less potent than enalapril and captopril in potentiating cough responses induced by capsaicin and citric acid in guinea-pigs, and further suggest that bradykinin might be a key substance in the mechanism of the potentiation of coughs associated with ACE inhibitors.     

Single dose and steady state pharmacokinetics and pharmacodynamics of the ACE-inhibitor imidapril in hypertensive patients

Aims To investigate the pharmacokinetic profile of the ACE-inhibitor imidapril in 10 hypertensive patients after a first single dose (10  mg) and after 28 days therapy with imidapril 10  mg once daily.
Methods C _max, t _max, t _1/2 and AUC of imidapril and imidaprilat were obtained. ACE-activity and arterial blood pressure during imidapril were corrected by a preceding placebo-investigation.
Results The AUC of imidapril was 140 (43  s.d.)  ng  ml⁻¹ h after the first dose and 123 (34  s.d.)  ng  ml⁻¹ h at steady state. AUC of the active moiety imidaprilat averaged 211 (101  s.d.)  ng  ml⁻¹ h after the first dose and 240 (55  s.d.)  ng  ml⁻¹ h at the steady state investigation. Maximal ACE-inhibition was 75% after the single dose as well as at steady state. ACE inhibition before drug intake at day 28 (i.e. trough) was 50%. The (placebo-corrected) maximal drop in diastolic blood pressure after imidapril was 22  mmHg after the first dose and 25  mmHg at steady state. Exploratory analysis of imidaprilat plasma concentration vs effect profiles suggests a hyperbolic concentration effect relationship where data of the single dose contribute to the ascending part of an E_max-curve, whereas the plateau around E_max is maintained at steady state.
Conclusions In this group of hypertensive patients, the pharmacokinetic profile and the drop in ACE-activity as well as in blood pressure seen after a single dose of imidapril and at steady state were similar. The initial response to a test dose might therefore predict the response during chronic dosing.     

Dose-finding study of imidapril,a novel angiotensin converting enzyme inhibitor,in patients with stable chronic heart failure

Objective: To study the haemodynamic profile and tolerability of imidapril, a new long-acting ACE inhibitor, and to investigate the effect of inhibition of circulating ACE on blood pressure in patients with stable chronic heart failure. Methods: Twenty-four patients with stable, chronic heart failure (New York Heart Association (NYHA) functional Class II–III) were randomised to receive either 2.5 mg or 5 mg imidapril. Other vasodilators were withheld for ≥ 5 half-lives. Blood pressure and ACE activity were carefully monitored for 24 h after dosing. Results: Both 2.5 mg and 5 mg imidapril decreased systolic blood pressure, while diastolic blood pressure fell only after 5 mg imidapril. The two doses produced a significant and similar inhibition of circulating (serum) ACE. No serious adverse effects were observed, although symptomatic hypotension occurred in 1 patient (5 mg). The decrease in blood pressure was not related to baseline ACE activity, serum sodium or serum creatinine concentration. Conclusions: Imidapril significantly lowered systolic blood pressure and was well tolerated. The difference in the first dose response to the two doses with respect to diastolic blood pressure suggests that this haemodynamic effect of ACE-inhibition is not related to inhibition of circulating ACE. Received: 21 April 1995/Accepted in revised form: 15 December 1995     

Studies on angiotensin I converting enzyme (ACE) inhibitory effect of imidapril. (I). Inhibition of various tissue ACEs in vitro]

Imidapril is a newly synthesized non-sulfhydryl-containing angiotensin I converting enzyme (ACE) inhibitor. The present study describes the inhibitory effects of imidapril and its active metabolite 6366A on ACEs from various tissues and compares its effects to those of captopril, enalapril and enalaprilat in vitro. 6366A inhibited swine renal and human serum ACEs with an inhibition constant (Ki) of 0.067 nM and 0.04 nM, respectively. These values were 3 to 18 times more potent than those of the other inhibitors. The kinetic study showed that 6366A exerted competitive type inhibition. The ACE inhibition (IC50 values) of 6366A, enalaprilat and the structurally related compounds (6366DM and 6366PY) were compared in homogenates of lung, aorta, heart, brain and kidney from spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs). The inhibitory effects of 6366A on all tissue ACEs from SHRs and WKYs were the most potent among these compounds. And the inhibitory potencies of these compounds were correlated with their chemical structure. The present results suggest that 6366A may show a strong inhibitory effect on ACEs from several tissues and species due to its chemical characteristics.     

Tissue Angiotensin-converting enzyme activity plays an important role in pressure overload-induced cardiac fibrosis in rats

It has been widely assumed that the cardiac angiotensin-generating system plays an important role in the development and maintenance of cardiac remodeling caused by pressure overload. The roles of angiotensin-converting enzyme (ACE) in pressure overload-induced cardiac hypertrophy and fibrosis in rats were investigated. Pressure overload was achieved by constricting the abdominal aorta above the renal arteries. After they underwent surgery, the rats were treated with a low or high dose of the ACE inhibitor imidapril (0.07 and 0.7 mg/kg/d s.c.) with an osmotic pump for 4 weeks. High-dose imidapril prevented the increase in blood pressure, cardiac hypertrophy, and fibrosis. Low-dose imidapril inhibited only cardiac fibrosis. ACE activity in the myocardium, but not in serum, was significantly increased in the rats with the banded aorta, and ACE immunoreactivity was increased in the areas of fibrosis. These changes were markedly reduced by both doses of imidapril. These results suggest that the increased local ACE expression contributes to the development of pressure overload-induced cardiac fibrosis but is not responsible for hypertrophy in rats.     

Pharmacokinetic and pharmacodynamic interaction trial after repeated oral doses of imdapril and digoxin in healthy volunteers

Aims To investigate the potential pharmacokinetic and pharmacodynamic interaction between imidapril and digoxin. Methods AUC, C_max and t_max of imidapril, imidaprilat and digoxin were calculated and evaluated in a randomized, doubleblind three-period cross-over design in 12 healthy volunteers after 8 days treatment with the following combinations: digoxin 0.25 mg day⁻¹+placebo (D+P); imidapril 10 mg day⁻¹+placebo (I+P); imidapril 10 mg day⁻¹+digoxin 0.25 mg day⁻¹ (I+D). Results Mean AUC (0, 24 h) of digoxin was 10.4 (±4.9 s.d.) ng ml⁻¹ h (D+P) and 10.7 (±3.9 s.d.) ng ml⁻¹ h (I+D), respectively (90%-confidence intervals [ CI] for the ratio of (D+P) and (I+D): 0.91–1.27, point estimator [PE]: 1.06). Mean AUC (0, 24 h) of imidapril was 133 (±86 s.d.) ng ml⁻¹ h (I+P) and 108 (±52 s.d.) ng ml⁻¹ h (I+D), respectively (90%-CI: 0.76–0.94, PE 0.85). AUC (0, 24 h) of imidaprilat was 215 (±91 s.d.) ng ml⁻¹ h (I+P) and 194 (±54 s.d.) ng ml⁻¹ h (I+D), respectively (90%-CI: 0.80–1.08, PE 0.93). C_max was 19.9 (±8.7 s.d.) ng ml⁻¹ (I+P) and 15.9 (±5.3 s.d.) ng ml⁻¹ (I+D) (90%-CI: 0.67–1.00, PE 0.82). The results indicate a slight reduction of imidapril and imidaprilat plasma levels when coadministered with digoxin without any effect on digoxin plasma levels. Maximal ACE-inhibition was 79% (I+P) and 67% (I+D). Conclusions Grouped data analysis of imidaprilat plasma levels vs ACE-activity showed that for maximal inhibition of plasma ACE activity, imidaprilat plasma levels should exceed 10 ng ml⁻¹. Under digoxin and imidapril, more plasma concentrations of imidaprilat were seen under this level as after imidapril alone, this reduces the integral of the ACE-inhibition/time curves by about 20 to 30%.     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 1st communication: absorption, pharmacokinetics and excretion in rats and dogs.

Imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) is an ester prodrug of the angiotensin-converting enzyme (ACE) inhibitor, 6366 A (CAS 89371-44-8). Absorption, pharmacokinetics and excretion of imidapril were studied in rats and dogs after oral and intravenous administration of [N-methyl-14C]-imidapril and [N-methyl-14C]-6366 A (1 mg/kg). Following oral administration of 14C-labeled imidapril and 6366 A to rats, plasma concentrations of radioactivity were much higher after [N-methyl-14C]-imidapril dosing than after [N-methyl-14C]-6366 A dosing at all time points. Imidapril was relatively rapidly absorbed from the digestive tract and easily metabolized to the pharmacologically active 6366 A after oral dosing in the rats and dogs. Thus, imidapril proved to be an orally usable 6366 A prodrug. More than 62% and 38% of the dose were assumed to be absorbed from the gastrointestinal tract in the rats and dogs, respectively. The in situ absorption study showed that [N-methyl-14C]-imidapril was absorbed from nearly the entire rat small intestine, especially from the jejunum, but hardly absorbed from the stomach. After oral administration, peak levels of radioactivity in the plasma occurred at 1 h in rats and 30 min to 2 h in dogs. The disappearance of unchanged drug from the plasma was much faster in rats than in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of pharmacokinetics and pharmacodynamics relationships for Salvianolic Acid B micro-porous osmotic pump pellets in angina pectoris rabbit

The work aims to investigate the in vitro release, pharmacokinetics (PK), pharmacodynamics (PD) and PK–PD relationships of Salvianolic Acid B micro-porous osmotic pump pellets (SalB-MPOPs) in angina pectoris New Zealand White (NZW) rabbits, compared with those of SalB immediate-release pellets (SalB-IRPs). The SalB plasma concentrations and Superoxide dismutase levels (PD index) were recorded continuously at predetermined time interval after administration, and the related parameters were calculated by using WinNonlin software. The release profile of MPOPs was more sustained than that of IRPs. PK results indicated that the mean C_max was significantly lower, the SalB plasma concentrations were steadier, both area under concentration-time curve from 0 to 24 h (AUC_0–24 h) and from 0 to infinity (AUC_0–∞) were presented larger, and both the peak concentration time (T_max) and mean residence time (MRT) were prolonged for MPOPs, as compared with those of IRPs. PD results suggested that peak drug effect (E_max) was lower and the equilibration rate constant (k_e0) between the central compartment and the effect compartment was higher of MPOPs vs. those of IRPs. PK–PD relationships demonstrated that the effect-concentration-time (ECT) course of MPOPs was clockwise hysteresis loop, and that of IRPs was counter-clockwise hysteresis loop. Collectively, those results demonstrated that MPOPs were potential formulations in treating angina pectoris induced by atherosclerosis.     

普鲁卡因胺经羧酸酯酶1对咪达普利代谢的影响

目的:研究普鲁卡因胺经羧酸酯酶1（CES1）影响咪达普利代谢的作用。方法:进行体外大鼠肝微粒体酶孵育实验,通过测定CES1特异性底物咪达普利的代谢产物咪达普利拉的含量,来研究普鲁卡因胺对CES1活性的影响;将12只SD大鼠随机分为两组,分别给予生理盐水和普鲁卡因胺(50mg·kg^-1),连续4 d,随后灌胃给予咪达普利(10mg·kg^-1),于给药后不同时间点采集血样,采用LC-MS/MS法测定血浆中咪达普利拉的含量,计算药动学参数,来研究普鲁卡因胺对咪达普利在大鼠体内代谢的影响。结果:在体外研究中,普鲁卡因胺对CES1的调节呈现剂量依赖型抑制特征。体内研究发现,普鲁卡因胺显著降低咪达普利拉AUC_0-24h,AUC_0-∞和C_max。结论:普鲁卡因胺显著抑制CES1的活性,从而抑制咪达普利拉的形成,对酯类前药代谢的研究有一定的意义。     

咪达普利在免疫性肝损伤大鼠体内的药动学特征

目的:探讨咪达普利在免疫性肝损伤大鼠体内的药动学特征。方法:采用腹腔注射卡介苗(BCG)和脂多糖(LPS)建立大鼠免疫性肝损伤模型。模型组和正常对照组分别灌胃给予咪达普利(10 mg·kg-1),于给药后不同时间点采血,采用LC-MS/MS法测定血浆中咪达普利代谢产物咪达普利拉的浓度,计算药动学参数。结果:与正常大鼠相比,免疫性肝损伤大鼠体内咪达普利拉的的AUC0-12h、AUC0-∞和Cmax显著降低(P<0.05)。结论:免疫性肝损伤状态下,咪达普利的水解代谢受到显著抑制,药动学发生明显改变,该作用可能与LPS抑制羧酸酯酶1(CES1)的活性相关。     

香青兰总黄酮渗透泵片的体外释放

目的:研究香青兰总黄酮渗透泵片的体外释放度。方法:采用相似因子(f2)法对香青兰中总黄酮释放曲线的相似性进行比较评价,考察不同溶出方法、溶出介质的种类和桨叶转速对香青兰总黄酮渗透泵片体外释放的影响。结果:采用桨法的小杯法,溶出介质为0.8%十二烷基硫酸钠溶液,桨叶转速为100r.min-1时,香青兰总黄酮渗透泵片的体外释药行为没有受到显著性影响。结论:香青兰总黄酮渗透泵片体外释药稳定,重复性好,控制释放特征明显     

Pharmacokinetic/pharmacodynamic modeling of the cardiovascular effects of beta blockers in humans

Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter "Keo" in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.     

Contribution of the tissue angiotensin converting enzyme to the antihypertensive effect of altiopril calcium (MC-838) in spontaneously hypertensive rats

The effect of a new orally active angiotensin converting enzyme (ACE) inhibitor, calcium (-)-N-[(S)-3-[(N-cyclohexylcarbonyl-D-alanyl)thio]-2-methylpropionyl+ ++]-L- prolinate (MC-838, altiopril calcium), on systemic blood pressure (SBP) and tissue ACE activity has been examined in conscious spontaneously hypertensive rats (SHRs). MC-838 (3 mg kg-1) given orally to SHRs elicited a long-lasting hypotension lasting over 24 h. With the development of the hypotension, MC-838 significantly reduced ACE activity in the lung, kidney and aorta, but not in the brain and heart. Suppression of plasma ACE and rise of plasma renin activity occurred only transiently at an earlier stage.