Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin

Abstract

Objective Because clinical data about the therapeutic consequences of polymorphic oxidation of simvastatin by CYP2D6 have not been well reported, we sought to investigate the possible link between polymorphism of CYP2D6 and the efficacy and tolerability of simvastatin treatment in a group of 88 patients with hypercholesterolemia. Methods TheCYP2D6 genotype was determined with use of polymerase chain reaction and restriction fragment analysis, whereas the CYP2D6 phenotype was determined by monitoring the dextromethorphan metabolism. Results Four of 5 patients with 2 defectiveCYP2D6 alleles discontinued the therapy at a low daily dose because of adverse events, with a significant mean decrease in the cholesterol levels of 0.23 mmol/L per milligram of simvastatin in the daily dose. In the group of 28 patients with 1 mutatedCYP2D6 gene, 13 did not tolerate the therapy, whereas a mean decrease in the cholesterol levels of 0.20 mmol/L per milligram of simvastatin was found. One patient with a multiplication of theCYP2D6 gene showed a cholesterol reduction of only 0.01 mmol/L per milligram of simvastatin, at a maximal daily dose of 40 mg. Only 9 patients of the group of 54 persons who were homozygous for the wild‐type allele discontinued the therapy because of intolerance. In that group, a mean decrease of cholesterol of 0.10 mmol/L per milligram of simvastatin was observed. Conclusions Our data provide evidence that the cholesterol‐lowering effect of simvastatin is influenced by CYP2D6 polymorphism. The clinical use of this knowledge may allow for more efficient individual therapies. Clinical Pharmacology & Therapeutics (2001) 70, 546–551; doi:

Safety of Statins

“…60 For example, findings indicate that CYP2D6 polymorphisms influence the efficacy and tolerability of simvastatin. 61 Conflicting data have been reported on the effect of statins on clopidogrel-inhibited platelet aggregation in patients undergoing coronary stenting; at the moment, there are no clear reasons to exclude the coadministration of these two classes of drugs in patients who are at high risk for coronary events. [62][63][64][65] …”

Clinical implications of pharmacogenomics of statin treatment

“…Variation in CYP2D6 has been associated with decreased adherence to simvastatin therapy, although the metabolic significance of this enzyme in simvastatin clearance is under debate. 23,25 The presence of the e4 allele of ApoE is associated with decreased adherence. 67 A case of rhabdomyolysisinduced death from cerivastatin exposure may have been caused by a loss of function mutation in CYP2C8 resulting in increased systemic exposure.…”

“…20 This finding was replicated in one of two subsequent studies, both of which enrolled less than 100 subjects. [21][22][23] These data are further complicated by conflicting reports as to the significance of CYP2D6 metabolism in simvastatin clearance. [24][25][26] Conflicting conclusions from individual studies are largely due to limited sample size as underpowered studies are less likely to yield reproducible results.…”

Correlation between CYP2D6*10 Gene Mutation, and Structure and Function of its Encoding Prot

“…Nordin found that a significant correlation between LDL-C reduction and reduced expression of CYP2D6 [15]. Mulder found that the cholesterol-lowering effect of simvastatin was influenced by CYP2D6 polymorphism [16]. However, Prueksaritanont concluded that the efficacy of simvastatin is not influenced by CYP2D6 polymorphism [17].…”