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On the possible relationship between the presence of polymorphic variants of CYP3A4/5 cytochrome genes, their metabolic activity with rivaroxaban pharmacokinetics and the development of bleeding in patients with non-valvular atrial fibrillation and chronic kidney disease
DOI: https://dx.doi.org/10.18565/pharmateca.2024.1.41-50
Shatalova N.A., Mirzaev K.B., Abdullaev Sh.P., Sozaeva Zh.A., Bochkov P.O., Asoskova A.V., Denisenko N.P., Kochetkov A.I., Ebzeeva E.Yu., Chernyaeva M.S., Shastina V.R., Ostroumova O.D., Sychev D.A.
1) Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 2) Hospital for War Veterans No. 2 of the Department of Health of Moscow, Moscow, Russia; 3) I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
Background. The administration of oral anticoagulants in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is associated with an increased risk of bleeding. Rivaroxaban is metabolised by several pathways, one of which is catalysed by cytochrome P-450 enzymes. Carrying polymorphic variants of genes encoding proteins of cytochrome P-450 system (CYP3A4, CYP3A5) and its metabolic activity may affect rivaroxaban concentration and, consequently, the risk of bleeding.
Objective: to assess the possible relationship between the presence of polymorphic variants of CYP3A5 (rs776746), CYP3A4 (rs35599367) genes, metabolic activity of CYP3A, Cmin,ss of rivaroxaban and bleeding in patients with non-valvular AF and concomitant CKD stages 3 and 4.
Methods. 122 patients from 52 to 97 years old (median age 82 years) with AF combined with CKD stages 3 and 4 were included in the study. Each patient was subjected to pharmacogenetic and pharmacokinetic study, and further the occurrence of bleeding was evaluated during 16 weeks using a special bleeding questionnaire. All patients were further divided according to genotype into «slow» (n=7), intermediate» (n=98) and «normal metaboliser» (n=17) groups followed by analyses of CYP3A metabolic activity, Cmin,ss of rivaroxaban and presence of bleeding events.
Results. During the follow-up period, 48 patients (39.3%) were found to have haemorrhages. The metabolic activity of CYP3A (6-β-hydroxycortisol/cortisol ratio) was statistically significantly higher in patients with bleeding compared to patients without bleeding: 0.8 [0.6; 1.6] and 0.7 [0.5; 1.6] ng/ml, respectively (p=0.046). CYP3A metabolic activity was paradoxically higher in the «slow metaboliser» group compared to the «intermediate» metaboliser group: 2.14 [1.42; 2.38] and 0.80 [0.53; 1.67] ng/ml, respectively (p=0.022).
Conclusion: the influence of rivaroxaban metabolism on the development of bleeding in patients with AF and CKD requires further study.
Objective: to assess the possible relationship between the presence of polymorphic variants of CYP3A5 (rs776746), CYP3A4 (rs35599367) genes, metabolic activity of CYP3A, Cmin,ss of rivaroxaban and bleeding in patients with non-valvular AF and concomitant CKD stages 3 and 4.
Methods. 122 patients from 52 to 97 years old (median age 82 years) with AF combined with CKD stages 3 and 4 were included in the study. Each patient was subjected to pharmacogenetic and pharmacokinetic study, and further the occurrence of bleeding was evaluated during 16 weeks using a special bleeding questionnaire. All patients were further divided according to genotype into «slow» (n=7), intermediate» (n=98) and «normal metaboliser» (n=17) groups followed by analyses of CYP3A metabolic activity, Cmin,ss of rivaroxaban and presence of bleeding events.
Results. During the follow-up period, 48 patients (39.3%) were found to have haemorrhages. The metabolic activity of CYP3A (6-β-hydroxycortisol/cortisol ratio) was statistically significantly higher in patients with bleeding compared to patients without bleeding: 0.8 [0.6; 1.6] and 0.7 [0.5; 1.6] ng/ml, respectively (p=0.046). CYP3A metabolic activity was paradoxically higher in the «slow metaboliser» group compared to the «intermediate» metaboliser group: 2.14 [1.42; 2.38] and 0.80 [0.53; 1.67] ng/ml, respectively (p=0.022).
Conclusion: the influence of rivaroxaban metabolism on the development of bleeding in patients with AF and CKD requires further study.
Keywords: CYP3A5, CYP3A4, rivaroxaban, pharmacokinetics, bleeding, chronic kidney disease, pharmacogenetics, anticoagulants, atrial fibrillation
About the Autors
Corresponding author: Olga D. Ostroumova, Dr. Sci, (Med.), Professor, Head of the Department of Therapy and Polymorbid Pathology n.a. Acad.
M.S. Vovsi, Russian Medical Academy of Continuous Professional Education; Professor at the Department of Clinical Pharmacology and Propaedeutics of Internal Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; ostroumova.olga@mail.ru
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