Modeling the Differential Effect of CYP2C9 Gene Alleles on Losartan Metabolism

Arterial hypertension is a multifactorial disease characterized by an increase in systolic and/or diastolic blood pressure. This pathology affects about a billion people worldwide. Hypertension is also a common risk factor for the development of different cardiovascular diseases, which are the leading cause of death in the population, claiming about 17 million lives annually. Various antihypertensive drugs are used to control hypertension, for example, losartan, a selective angiotensin II AT1-receptor antagonist. Losartan is primarily metabolized in the liver by CYP2C9, a member of the cytochrome P450 superfamily, to the pharmacologically active metabolite carboxylosartan (E-3174). The CYP2C9 gene is highly polymorphic: numerous single nucleotide polymorphisms that alter the function of the enzyme 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. It was shown that, depending on the CYP2C9 genotype, the pharmacokinetics of losartan and E-3174 differ significantly, which is confirmed by previously published experimental data. To develop and analyze the model, we used the BioUML software. The results of the modeling can potentially be used to personalize drug therapy for arterial hypertension.