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ORIGINAL RESEARCH article
Front. Syst. Biol.
Sec. Multiscale Mechanistic Modeling
Volume 5 - 2025 | doi: 10.3389/fsysb.2025.1504077
This article is part of the Research TopicHot Topics 2023: Multiscale Mechanistic Modelling to Predict Cellular and Physiological Drug ResponsesView all articles
Mathematical modeling of pharmacokinetics and pharmacodynamics of losartan in relation to CYP2C9 allele variants
Provisionally accepted- Sirius University, Sochi, Russia
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Losartan is a selective angiotensin II AT1-receptor antagonist for the treatment of arterial hypertension and heart failure. It is converted to pharmacologically active metabolite carboxylosartan (E-3174) in the liver mainly by CYP2C9 enzyme, a member of the cytochrome P450 superfamily. The gene encoding this protein is highly polymorphic: numerous single nucleotide polymorphisms that alter the enzyme function have been described in the literature. The most widespread CYP2C9 alleles are CYP2C9*1 (wild-type), CYP2C9*2 and CYP2C9*3.Here we performed mathematical modeling of the metabolism of orally administered losartan to E-3174 taking into account combinations of the most common CYP2C9 alleles. Next, using the previously created model of the human cardiovascular and renal systems, we demonstrated that the blood pressure response to losartan therapy in a cohort of virtual hypertensive patients depended on CYP2C9 allelic variants. Individuals with the CYP2C9*1/CYP2C9*1 genotype responded better to treatment than patients carrying CYP2C9*2 or CYP2C9*3 alleles. The results of the modeling can potentially be used for personalization of drug therapy for arterial hypertension.*P-value < 1E-03 vs. CYP2C9*1/CYP2C9*1. **P-value < 1E-10 vs. CYP2C9*1/CYP2C9*1.Comparisons were performed by unpaired Student's t-test using the Bonferroni cutoff for significance (Pvalue < 0.0083, i.e., 0.05/number of CYP2C9 genotypes).
Keywords: arterial hypertension, Losartan, pharmacokinetics, Pharmacodynamics, CYP2C9, mathematical modeling, Biouml, personalized medicine
Received: 30 Sep 2024; Accepted: 11 Apr 2025.
Copyright: © 2025 Babaev, Kutumova and Kolpakov. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dmitry Babaev, Sirius University, Sochi, Russia
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