Genetic polymorphisms in cytochrome P450 enzymes: effect on efficacy and tolerability of HMG-CoA reductase inhibitors.
Adverse drug reactions are common; they are responsible for a number of debilitating side effects and are a significant cause of death following drug therapy. It is now clear that a significant proportion of these adverse drug reactions, as well as therapeutic failures, are caused by genetic polymorphism, genetically based interindividual differences in drug absorption, disposition, metabolism, or excretion. HMG-CoA reductase inhibitors are generally very well tolerated and easy to administer with good patient acceptance. There are only two uncommon but potentially serious adverse effects related to HMG-CoA reductase inhibitor therapy: hepatotoxicity and myopathy. The occurrence of lethal rhabdomyolysis in patients treated with cerivastatin has prompted concern on the part of physicians and patients regarding the tolerability of HMG-CoA reductase inhibitors. Apart from pravastatin and rosuvastatin, HMG-CoA reductase inhibitors are metabolized by the phase I cytochrome P450 (CYP) superfamily of drug metabolizing enzymes. The best-characterized pharmacogenetic polymorphisms are those within this enzyme family. One of these enzymes, CYP2D6, plays an important role in the metabolism of simvastatin. It has been shown that the cholesterol-lowering effect as well as the efficacy and tolerability of simvastatin is influenced by CYP2D6 genetic polymorphism. Because the different HMG-CoA reductase inhibitors differ, with respect to the degree of metabolism by the different CYP enzymes, genotyping may help to select the appropriate HMG-CoA reductase inhibitor and the optimal dosage during the start of the treatment and will allow for more efficient individual therapy. A detailed knowledge of the genetic basis of individual drug response is potentially of major clinical and economic importance.
Department of Clinical Pharmacy, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Andras
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Vermes
Istvan
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Vermes
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System