engleski

ABCG2 and CYP3A4 polymorphisms as a risk factors for developing adverse drug reactions in patients taking atorvastatin: a case-control study

Background: Statins are among the most prescribed drugs, with atorvastatin being the most frequently used statin. Although statins have been confirmed to be well tolerated agents, there is significant number of people who are intolerant of statin therapy or who suffer side effects. ABCG2 is efflux transporter of a wide variety of xenobiotics, among which are some classes of statins. Among other functions, ABCG2 limits the absorption of its substrates from the gut and increases the excretion into the bile and urine. Its polymorphism, c.421C>A, has been associated with reduced ABCG2 transport activity. CYP3A4*22 variant could have influence on atorvastatin metabolism. Objective of the study was to explore the association between most commonly reported ADRs (adverse drug reactions) of atorvastatin (miotoxicity and hepatotoxicity) and polymorphism of ABCG2 and CYP3A4 gene. Myotoxicity and hepatotoxicity were investigated together as these ADRs are related to plasma concentration and influenced by changes in the pharmacoki­netics of statins. Patients and Methods: Sixty patients who experienced atorvastatin-related mytoxicity or hepatotoxicity and sixty matched patients without ADRs were enrolled in the study. Data regarding age, sex, atorvastatin dose, concomitant drugs, comorbidities, data regarding risk factors for atorvastatin ADRs (hepatic or renal dysfunction, perioperative periods, multisystem diseases, small body size and untreated hypothy­roidism) were collected. Genotyping for ABCG2 421 CCYP3A4*22 variants was performed by real-time PCR methods. Results: The results showed that those having ABCG2 421CA genotype had 3.8-times greater odds of experiencing atorvastatin-related ADRs (χ2=7.222 ; df=2 ; p=0.015 ; Cramer’s φ=0.245, odds ratio [OR]=3.75 ; CI: 1.27-11.12) than those with ABCG2 421CC genotype. 3 patients who developed ADRs were and patient from control group were CYP3A4*22 carriers. After adjustments for clinical risk factors, influence of ABCG2 421C>A remained a sta­ tistically significant predictor of adverse effects (OR=3, 79 ; Wald c2=5.39 ; df=1 ; p=0.020 ; 95% CI: 1.23–11.69). Conclusion: Our results demonstrate an association between atorvastatin- induced ADRs and genetic variants in the ABCG2. Influence of CYP3A4*22 variants should be further investigated in bigger studies.

ABCG2; adverse drug reactions; atorvastatin; CYP3A4

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