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

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Abstract

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.

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About the authors

N. A. Shatalova

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0001-6823-6077
Russian Federation, Moscow

K. B. Mirzaev

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0002-9307-4994
Russian Federation, Moscow

Sh. P. Abdullaev

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0001-9001-1499
Russian Federation, Moscow

Zh. A. Sozaeva

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
Russian Federation, Moscow

P. O. Bochkov

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0001-8555-5969
Russian Federation, Moscow

A. V. Asoskova

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0002-2228-8442
Russian Federation, Moscow

N. P. Denisenko

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0003-3278-5941
Russian Federation, Moscow

A. I. Kochetkov

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0001-5801-3742
SPIN-code: 9212-6010
Russian Federation, Moscow

E. Yu. Ebzeeva

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0001-6573-4169
Russian Federation, Moscow

M. S. Chernyaeva

Hospital for War Veterans No. 2 of the Department of Health of Moscow

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0003-3091-7904
Russian Federation, Moscow

V. R. Shastina

Hospital for War Veterans No. 2 of the Department of Health of Moscow

Email: ostroumova.olga@mail.ru
Russian Federation, Moscow

Olga D. Ostroumova

Russian Medical Academy of Continuous Professional Education; I.M. Sechenov First Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0002-0795-8225
SPIN-code: 3910-6585

Dr. Sci, (Med.), Professor, Head of the Department of Therapy and Polymorbid Pathology n.a. Acad. M.S. Vovsin, Professor at the Department of Clinical Pharmacology and Propaedeutics of Internal Diseases

Russian Federation, Moscow; Moscow

D. A. Sychev

Russian Medical Academy of Continuous Professional Education

Email: ostroumova.olga@mail.ru
ORCID iD: 0000-0002-4496-3680
SPIN-code: 4525-7556
Russian Federation, Moscow

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