A Saturable Tissue-Angiotensin I Converting Enzyme (ACE) Binding Model for the Pharmacokinetic Analysis of Imidapril, a New ACE Inhibitor, and Its Active Metabolite in Human.

Abstract

In order to obtain a rational explanation and analytical method of the unique pharmacokinetic behaviors of imidapril and imidaprilat in human, a new pharmacokinetic model was designed by introducing a saturable-reversible angiotensin I converting enzyme (ACE)-imidaprilat binding process and a linear imidapril-imidaprilat conversion process. According to the new model, six differential equations were given which considered the mass balance of both compounds in each component. Various pharmacokinetic parameters were estimated by the simultaneous curve fitting method using the plasma concentration data and the urinary excretion data of imidapril and imidaprilat in a multiple dosing study of healthy human volunteers. To validate the value of each parameter, this pharmacokinetic model was also applied to analyze the various plasma concentration data of both compounds in the single dosing studies with four different dosages, 2.5,5, 10, and 20 mg. Excellent curve fitting was obtained in every case, suggesting that the proposed pharmacokinetic model is applicable for predicting the plasma concentrations of imidapril and imidaprilat under various dosage conditions of clinical use.

Val‐Tyr As A Natural Antihypertensive Dipeptide Can Be Absorbed Into The Human Circulatory Blood System

“…Therefore, intact VY absorption was estimated to be much slower than that of other peptides 20 . This slow absorption of VY is comparable with that of the clinical ACE inhibitor imidapril, for which maximal plasma concentrations have been observed 2 h after administration to healthy human volunteers 21 18 …”

Absorption of Val-Tyr with in Vitro Angiotensin I-Converting Enzyme Inhibitory Activity into the Circulating Blood System of Mild Hypertensive Subjects.

“…16) Oral administration study of prodrug-type ACE inhibitor, imidapril, to healthy human, 17) on the other hand, demonstrated that the plasma concentration reached a maximal level (C max at 10 mg-dose) of 70 pmol/ml-plasma after 2 h (T max ; 2 h). While the absorption profile of imidapril with T max of 2 h was in good agreement with that in our present VY-study (Fig.…”

Electrocardiographic Changes and Mortality Due to Myocardial Infarction in Rats With or Without Imidapril Treatment

“…Imidapril ( 1 mg/kg) was administered by gastric tube daily. The selection of dose and route of administration of this agent are based on previous studies ( 19,20,23). Such treatment of infarcted rats with imidapril has been shown to prevent the activation of cardiac and circulating ACE.…”

“…Imidapril, (4S)-l-methyl-3-((2S)-2-[N-((IS)-l-ethoxycarbonyl-3-phenylpropyl)-amino] propionyl)-2-oxo-imidazolidine-4-carboxylic acid, is a non-sulfhydryl-containing ACE inhibitor similar to enalapril (18)(19)(20). We studied the effects of imidapril in rats because the time course for arrhythmias and mortality during acute myocardial infarction are well characterized in this species (21).…”