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Processes 2019, 7(3), 131; https://doi.org/10.3390/pr7030131

A Glucose-Dependent Pharmacokinetic/ Pharmacodynamic Model of ACE Inhibition in Kidney Cells

1
School of Chemical Engineering, Oklahoma State University, Stillwater, OK 74078, USA
2
Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
*
Author to whom correspondence should be addressed.
Received: 29 January 2019 / Revised: 22 February 2019 / Accepted: 25 February 2019 / Published: 4 March 2019
(This article belongs to the Special Issue Systems Biomedicine)
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Abstract

Diabetic kidney disease (DKD) is a major cause of renal failure. Podocytes are terminally differentiated renal epithelial cells that are key targets of damage due to DKD. Podocytes express a glucose-stimulated local renin-angiotensin system (RAS) that produces angiotensin II (ANG II). Local RAS differs from systemic RAS, which has been studied widely. Hyperglycemia increases the production of ANG II by podocyte cells, leading to podocyte injury. Angiotensin-converting enzyme (ACE) is involved in the production of ANG II, and ACE inhibitors are drugs used to suppress elevated ANG II concentration. As systemic RAS differs from the local RAS in podocytes, ACE inhibitor drugs should act differently in local versus systemic contexts. Experimental and computational studies have considered the pharmacokinetics (PK) and pharmacodynamics (PD) of ACE inhibition of the systemic RAS. Here, a PK/PD model for ACE inhibition is developed for the local RAS in podocytes. The model takes constant or dynamic subject-specific glucose concentration input to predict the ANG II concentration and the corresponding effects of drug doses locally and systemically. The model is developed for normal and impaired renal function in combination with different glucose conditions, thus enabling the study of various pathophysiological conditions. Parameter uncertainty is also analyzed. Such a model can improve the study of the effects of drugs at the cellular level and can aid in development of therapeutic approaches to slow the progression of DKD. View Full-Text
Keywords: PK/PD; podocytes; renin-angiotensin system; benazepril; diabetic kidney disease; diabetic nephropathy PK/PD; podocytes; renin-angiotensin system; benazepril; diabetic kidney disease; diabetic nephropathy
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Pilvankar, M.R.; Yong, H.L.; Ford Versypt, A.N. A Glucose-Dependent Pharmacokinetic/ Pharmacodynamic Model of ACE Inhibition in Kidney Cells. Processes 2019, 7, 131.

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