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.
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.
Tagawa
K
K
Pharmaceutics Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Mizobe
M
M
Noda
K
K
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics*; D001682:Biological Availability; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D048289:Imidazolidines; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D012044:Regression Analysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; C065166:imidapril; D007703:Peptidyl-Dipeptidase A; C078006:imidaprilat