Povezanost polimorfizma CYP2C9 s dozom i komplikacijama terapije oralnim antikoagulansom varfarinom [Association between CYP2C9 polymorphism and warfarin anticoagulant therapy dose and complications ]

Samardžija, Marina (2005) Povezanost polimorfizma CYP2C9 s dozom i komplikacijama terapije oralnim antikoagulansom varfarinom [Association between CYP2C9 polymorphism and warfarin anticoagulant therapy dose and complications ]. PhD thesis, Medicinski fakultet.

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Abstract

In vitro studies show association between alleles CYP2C9 *2, *3 and significantly reduced metabolism of various CYP2C9 substrates in comparison with the wild type. Warfarin is drug of choice among oral anticoagulant agents, and it is substrate for CYP2C9. The aim of the study was to determine kind and significance of the association between CYP2C9 polymorphism and warfarin anticoagulant therapy dose and complications. Study included the experimental group of patients receiving chronic oral anticoagulation therapy, 102 women, 79 men, and the control group of healthy persons, 26 women, 160 men. They underwent genotyping of CYP2C9 by PCR-RFLP using blood samples. The patients were determined prothrombin time (PT) 72 hours following induction of warfarin therapy, and repeatedly depending on the stability of PT. The required therapeutic level was considered INR 2.0-3.0. The patients were divided into the subgroups according to the following criteria: age (younger and equal to 65 years, older than 65 years), gender, maintenance daily warfarin dose (less or equal to 1.5 mg, more than 1.5 mg), INR by induction (less or equal to 3.5, between 3.6 and 5.0, more than 5.0), occurrence and severity of bleeding complications (without bleeding, minor bleeding, significant bleeding), underlying illness, CYP2C9 genotype and allelic variants. Frequencies of alleles in the healthy group of examinees were 84.1% for allele *1, 11.5% for allele *2 , and 4.0% for allele *3. CYP2C9 allele distribution in healthy population is concordant to other authors for caucasian. The groups of patients with the higher and the lower warfarin dose were not significantly different regarding the CYP2C9 genotypes (Pearson Chi-square=11.006, p=0.051), despite marginal significance of differences. In comparison with the optimal daily warfarin dose for those bearing the wild type genotype (100%), optimal daily warfarin dose in 2C9*2 heterozygotes was 92%, 74% in 2C9*3 heterozygotes, 61% in 2C9*2 homozygotes, 34% in 2C9*3 homozygotes and 63% in 2C9*2 and 2C9*3 heterozygotes. Our findings are concordant to other authors. The optimal daily doses were significantly different between the wild type and genotype *1/*3 (p=0.022). However, the age and gender related subgroups were significantly different in the optimal daily warfarin dose. The older subgroup and female received lower warfarin doses. The bleeding complications were not depend to CYP2C9*2, *3 alleles and genotypes, age and the underlying illness for chronic anticoagulation therapy. Bleeding was more often in those with INR greater than 5.0. Genotyping seems to be justified in the case of administration of a drug that is substrate for polymorphic enzyme.

Abstract in Croatian

In vitro istraživanja pokazuju da su aleli CYP2C9 *2 i *3 povezani sa značajno smanjenim metabolizmom različitih supstrata CYP2C9 u odnosu na divlji tip. Među oralnim antikoagulansima lijek izbora je varfarin koji je supstrat CYP2C9. Cilj ovog ispitivanja je bio utvrditi povezanost polimorfizma CYP2C9 s dozom i komplikacijama terapije oralnim antikoagulansom varfarinom. U ispitivanje je bilo uključeno 102 žene i 79 muškaraca u skupini bolesnika na terapiji varfarinom, te 26 žena i 160 muškaraca u kontrolnoj skupini. Genotipizacija CYP2C9 je rađena metodom PCR-RFLP iz uzoraka krvi. Bolesnicima je određivano protrombinsko vrijeme (PV) 72 sata po uvođenju lijeka, a učestalost praćenja je ovisila o stabilnosti PV-a. Terapijski optimum je iznosio 2,0-3,0 INR-a. Bolesnici su podijeljeni u podskupine prema slijedećim karakteristikama: dobi (≤65 godina, >65 godina), spolu, optimalnoj dnevnoj dozi varfarina (≤1,5 mg, >1,5 mg), INR-u u indukciji (≤3,5, 3,6-5,0, >5,0), pojavi i jačini krvarena (bez krvarenja, beznačajna i značajna krvarenja), dijagnozama, genotipu i alelima CYP2C9. Učestalost alela CYP2C9 *1 naše populacije u skupini zdravih ispitanika iznosi 84.1%, alela *2 11.5% i alela*3 4.0%. Naši rezultati za alele CYP2C9 u zdravoj populaciji u skladu su s podacima iz literature za bijelu populaciju. Genotipovi CYP2C9 se statistički značajno ne razlikuju između skupine bolesnika na dozi varfarina >1.5 mg i skupine bolesnika na dozi varfarina ≤1.5 mg, iako je razlika na granici značajnosti (χ²=11.006, p=0.051). Optimalna dnevna doza varfarina u 2C9*2 heterozigota iznosi 92% optimalne dnevne doze u odnosu na divlji tip, 74% u 2C9*3 heterozigota, 61% u 2C9*2 homozigota, 34% u 2C9*3 homozigota i 63% u 2C9*2 i *3 heterozigota. Naši podaci podudaraju se s podacima iz literature. Statistički značajno niža optimalna dnevna doza varfarina je u bolesnika s genotipom *1/*3 u odnosu na divlji tip (p=0.022). Optimalna doza varfarina je niža u žena u odnosu na muškarce i u osoba starijih od 65 godina u odnosu na mlađe od 65 godina. Pojava krvarenja ne ovisi o prisutnosti alela CYP2C9*2 i *3, genotipu CYP2C9, dobi bolesnika niti dijagnozama. Pojava krvarenja je češća u osoba s INR-om >5.0. Čini se prihvatljivo da genotipizacija može biti indicirana u svakom slučaju kad je lijek izbora supstrat za polimorfni enzim.

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