ArticleFrontiers in physiology2013
A detailed physiologically based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine Renin-Angiotensin-aldosterone system.
Article in Frontiers in physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed.
- Angiotensin II/Angiotensin I Ratio as a New Pharmacodynamic Parameter for Population Modelling in Healthy Adults and Children with Heart Failure Treated with Enalapril.Pharmaceutics · 2025Article
- Simultaneously Predicting the Pharmacokinetics of CES1-Metabolized Drugs and Their Metabolites Using Physiologically Based Pharmacokinetic Model in Cirrhosis Subjects.Pharmaceutics · 2024Article
- Adapting physiologically-based pharmacokinetic models for machine learning applications.Scientific reports · 2023Article
- A Comprehensive Whole-Body Physiologically Based Pharmacokinetic Model of Dabigatran Etexilate, Dabigatran and Dabigatran Glucuronide in Healthy Adults and Renally Impaired Patients.Clinical pharmacokinetics · 2019Article
- A computational analysis of the long-term regulation of arterial pressure.F1000Research · 2013Article
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5 authors.
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Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathogenesis of cardiovascular disorders including hypertension and is one of the most important targets for drugs. A whole body physiologically based pharmacokinetic (wb PBPK) model integrating this hormone circulation system and its inhibition can be used to explore the influence of drugs that interfere with this system, and thus to improve the understanding of interactions between drugs and the target system. In this study, we describe the development of a mechanistic RAAS model and exemplify drug action by a simulation of enalapril administration. Enalapril and its metabolite enalaprilat are potent inhibitors of the angiotensin-converting-enzyme (ACE). To this end, a coupled dynamic parent-metabolite PBPK model was developed and linked with the RAAS model that consists of seven coupled PBPK models for aldosterone, ACE, angiotensin 1, angiotensin 2, angiotensin 2 receptor type 1, renin, and prorenin. The results indicate that the model represents the interactions in the RAAS in response to the pharmacokinetics (PK) and pharmacodynamics (PD) of enalapril and enalaprilat in an accurate manner. The full set of RAAS-hormone profiles and interactions are consistently described at pre- and post-administration steady state as well as during their dynamic transition and show a good agreement with literature data. The model allows a simultaneous representation of the parent-metabolite conversion to the active form as well as the effect of the drug on the hormone levels, offering a detailed mechanistic insight into the hormone cascade and its inhibition. This model constitutes a first major step to establish a PBPK-PD-model including the PK and the mode of action (MoA) of a drug acting on a dynamic RAAS that can be further used to link to clinical endpoints such as blood pressure.
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