Drugs online research references
Rev Med Liege. 2001 Aug;56(8):592-4.
[Fatal rhabdomyolysis caused by cerivastatin]
[Article in French]
Scheen AJ.
Cerivastatin was recently withdrawn from the market after the report of more than 30 deaths in the United-States among patients receiving a combination of cerivastatin and gemfibrozil, a fibrate which is not anymore on the Belgian market. The cause of death was attributed to severe rhabdomyolysis. Cases were also reported among patients treated by cerivastatin only. Recommendations for better use of lipid-lowering drugs are given in order to optimize the benefit/risk ratio of such treatment.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11584446&dopt=Abstract
Drug Metab Dispos. 2001 Nov;29(11):1359-61.
Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9.
Wen X, Wang JS, Backman JT, Kivisto KT, Neuvonen PJ.
Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, FIN-00290 Helsinki, Finland.
The in vitro inhibitory effects of gemfibrozil on cytochrome P450 (CYP) 1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2C19 (S-mephenytoin 4'-hydroxylation), CYP2D6 (dextromethorphan O-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (midazolam 1'-hydroxylation) activities were examined using pooled human liver microsomes. The in vivo drug interactions of gemfibrozil were predicted in vitro using the [I]/([I] + K(i)) values. Gemfibrozil strongly and competitively inhibited CYP2C9 activity, with a K(i) (IC(50)) value of 5.8 (9.6) microM. In addition, gemfibrozil exhibited somewhat smaller inhibitory effects on CYP2C19 and CYP1A2 activities, with K(i) (IC(50)) values of 24 (47) microM and 82 (136) microM, respectively. With concentrations up to 250 microM, gemfibrozil showed no appreciable effect on CYP2A6, CYP2D6, CYP2E1, and CYP3A4 activities. Based on [I]/([I] + K(i)) values calculated using peak total (or unbound) plasma concentration of gemfibrozil, 96% (56%), 86% (24%), and 64% (8%) inhibition of the clearance of CYP2C9, CYP2C19, and CYP1A2 substrates could be expected, respectively. In conclusion, gemfibrozil inhibits the activity of CYP2C9 at clinically relevant concentrations, and this is the likely mechanism by which gemfibrozil interacts with CYP2C9 substrate drugs, such as warfarin and glyburide. Gemfibrozil may also impair clearance of CYP2C19 and CYP1A2 substrates, but inhibition of other CYP isoforms is unlikely.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11602509&dopt=Abstract
Jpn Heart J. 1996 Jan;37(1):119-26.
Persistence of balloon-induced arterial injury with hyperlipidemia despite gemfibrozil.
Lundgren C, Sobel BE, Fujii S.
Division of Cardiology, Wahington University School of Medicine, St. Louis, Missouri 63110, USA.
Restenosis after balloon dilitation of atherosclerotic arteries reflects migration and proliferation of vascular smooth muscle cells and infiltration of monocyte/macrophages. Hypercholesterolemia may contribute to this phenomenon. Accordingly, we used the lipid-lowering agent gemfibrozil to determine whether potentially detrimental effects of hypercholesterolemia on vascular remodeling after mechanical injury could be attenuated. New Zealand white rabbits fed either a chow diet (control), a 0.25% cholesterol-enriched diet, or a 0.25% cholesterol-enriched diet supplemented with gemfibrozil (0.05%, 0.1%, or 0.02%) for one week were subjected to balloon-induced carotid injury and maintained on the same diet for an additional 4 weeks. Histology of the vascular wall was then characterized. Plasma triglycerides before and 4 weeks after injury did not change in any of the treatment groups (p = 0.24). Plasma cholesterol increased in all animals receiving the high cholesterol diet, and the increases remained unaffected by supplementation with gemfibrozil. In control rabbits, intimal thickening area [intima (mm2)/(intima + media (mm2))] 4 weeks after injury was 27.0 +/- 7.7% (n = 16). Values were the same in hypercholesterolemic rabbits (29.7 +/- 11.8%, n = 12; p = ns). However, in 16% the lumen was completely occluded by thrombus and intimal thickening could not be quantified. In hypercholesterolemic rabbits given gemfibrozil, intimal thickening was increased by 33% compared with controls (35.9 +/- 11.6%, n = 39, pound 0.05) and by 21% compared with hypercholesterolemic animals not given gemfibrozil (p = ns). None had thrombotic luminal occlusion. Macrophages detected immunohistochemically were only modest in number in vessels from control animals. In vessels from hypercholesterolemic animals and from animals whose diets were supplemented with gemfibrozil, macrophages were increased in number in both intima and media. Thus, gemfibrozil did not appear to attenuate processes implicated in restenosis. Its attenuation of thrombotic occlusion may be related to effects we have noted it exerts on fibrinolytic systems independent of lipid metabolism.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8632619&dopt=Abstract
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