A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system
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 a...
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doaj-ef0c720d57a64fd3a9a13d1240f59ebd2020-11-24T22:01:16ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2013-02-01410.3389/fphys.2013.0000433293A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone systemKarina eClaassen0Karina eClaassen1Stefan eWillmann2Thomas eEissing3Tobias ePreusser4Tobias ePreusser5Michael eBlock6Jacobs University BremenBayer Technology Services GmbHBayer Technology Services GmbHBayer Technology Services GmbHJacobs University BremenFraunhofer MEVISBayer Technology Services GmbHThe 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 to 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.http://journal.frontiersin.org/Journal/10.3389/fphys.2013.00004/fullEnalaprilEnalaprilatcardiovascularPhysiologically-based pharmacokinetic modelrenin-angiotensin-aldosterone system |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Karina eClaassen Karina eClaassen Stefan eWillmann Thomas eEissing Tobias ePreusser Tobias ePreusser Michael eBlock |
spellingShingle |
Karina eClaassen Karina eClaassen Stefan eWillmann Thomas eEissing Tobias ePreusser Tobias ePreusser Michael eBlock A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system Frontiers in Physiology Enalapril Enalaprilat cardiovascular Physiologically-based pharmacokinetic model renin-angiotensin-aldosterone system |
author_facet |
Karina eClaassen Karina eClaassen Stefan eWillmann Thomas eEissing Tobias ePreusser Tobias ePreusser Michael eBlock |
author_sort |
Karina eClaassen |
title |
A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system |
title_short |
A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system |
title_full |
A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system |
title_fullStr |
A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system |
title_full_unstemmed |
A detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system |
title_sort |
detailed physiologically-based model to simulate the pharmacokinetics and hormonal pharmacodynamics of enalapril on the circulating endocrine renin-angiotensin-aldosterone system |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2013-02-01 |
description |
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 to 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. |
topic |
Enalapril Enalaprilat cardiovascular Physiologically-based pharmacokinetic model renin-angiotensin-aldosterone system |
url |
http://journal.frontiersin.org/Journal/10.3389/fphys.2013.00004/full |
work_keys_str_mv |
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