Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin.
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
The CYP2D6 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 defective CYP2D6 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 mutated CYP2D6 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 the CYP2D6 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.
Mulder
A B
AB
Department of Clinical Chemistry, Medical Spectrum Twente, Hospital Group, Enschede, The Netherlands.
van Lijf
H J
HJ
Bon
M A
MA
van den Bergh
F A
FA
Touw
D J
DJ
Neef
C
C
Vermes
I
I
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D019821:Simvastatin / Q000009:adverse effects / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D004247:DNA; D019821:Simvastatin; D019389:Cytochrome P-450 CYP2D6