Drug interactions with HMG-CoA reductase inhibitors (statins): the importance of CYP enzymes, transporters and pharmacogenetics.
HMG-CoA reductase inhibitors (statins) can cause skeletal muscle toxicity; the risk of toxicity is elevated by drug interactions and pharmacogenetic factors that increase the concentration of statins in the plasma. Statins are substrates for several membrane transporters that may mediate drug interactions. Inhibitors of the organic anion transporting polypeptide 1B1 can decrease the hepatic uptake of many statins, as well as the therapeutic index of these agents. Potent inhibitors of cytochrome P450 (CYP)3A4 can significantly increase the plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin. Fluvastatin, which is metabolized by CYP2C9, is less prone to pharmacokinetic interactions, while pravastatin, rosuvastatin and pitavastatin are not susceptible to any CYP inhibition. An understanding of the mechanisms of statin interactions will help to minimize drug interactions and to develop statins that are less prone to adverse interactions.
Neuvonen
Pertti J
PJ
University of Helsinki and Helsinki University Central Hospital, Department of Clinical Pharmacology, PO Box 705, FIN-00029 HUS, Helsinki, Finland. pertti.neuvonen@hus.fi
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions / Q000235:genetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010597:Pharmacogenetics
D065607:Cytochrome P-450 Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; D003577:Cytochrome P-450 Enzyme System