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. 2023 Feb 26;13:3300. doi: 10.1038/s41598-023-30453-x

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Detailed model diagram. Detailed diagram of the final model structure. Benazeprilat pharmacokinetics were modeled using a 2-compartment model with a mix of 1-order and 1-order delayed by 1-order transfer absorption from the depot compartment. Both volumes of distribution, free and tissue, were modeled with a fixed amount of ACE with which Benazeprilat could act on. Non-specific binding affected the free circulation compartment. A series of direct response models were used to describe the transformation of angiotensin I into its various metabolites. The free volume of distribution was subdivided into plasma and kidney volumes for Ang III and Ang IV. A Michaelis–Menten kinetic model of inhibitor, substrate, and enzyme interaction was used to describe the competitive inhibition of ACE by benazeprilat. k₃ and k_-3 were the parameters governing ACE-benazeprilat (enzyme-inhibitor) association and dissociation, while k₁ and k_-1 determined the rate of ACE-angiotensin (enzyme–substrate) association and dissociation. k₂ controlled the production rate of angiotensin II from angiotensin I via ACE. An independent clearance for each metabolite as well as benazeprilat controlled the rate of removal of various molecules from the plasma.