ABSTRACT
Because statins and ajoene inhibit the 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, we evaluated the hypothesis that the cytotoxic effect of these compounds may be potentiated when both are used in combination on tumor cells. We showed that cotreatment of the murine melanoma B16F10 cell with statins (atorvastatin and pravastatin) and ajoene, all at nontoxic doses, dramatically increased their cytotoxicity. B16F10 cell death induced by statins, but not by ajoene, was prevented by mevalonate and geranylgeranylpyrophosphate. To our knowledge, this is the first report that the combination of statins and ajoene, which alters the mevalonate pathway, might potentiate their cytotoxic effects on tumor cells.
Subject(s)
Disulfides/pharmacology , Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Melanocytes/drug effects , Melanoma, Experimental/pathology , Pravastatin/pharmacology , Pyrroles/pharmacology , Animals , Apoptosis/drug effects , Atorvastatin , Cell Line, Tumor/drug effects , Disulfides/antagonists & inhibitors , Disulfides/pharmacokinetics , Drug Screening Assays, Antitumor , Drug Synergism , Flow Cytometry , Heptanoic Acids/antagonists & inhibitors , Heptanoic Acids/pharmacokinetics , Mevalonic Acid/pharmacology , Mice , Polyisoprenyl Phosphates/pharmacology , Pravastatin/antagonists & inhibitors , Pravastatin/pharmacokinetics , Pyrroles/antagonists & inhibitors , Pyrroles/pharmacokinetics , Sulfoxides , Terpenes/metabolismABSTRACT
Coadministration of gemfibrozil (600 mg, b.i.d., 3 days) with pravastatin (40 mg/day) decreased the renal clearance of pravastatin by approximately 40% in healthy volunteers. To investigate the mechanism of this drug-drug interaction in the renal excretion process, we undertook an uptake study of pravastatin using human organic anion transporters (hOATs)-expressing S2 cells. hOAT3 and hOAT4 transported pravastatin in a saturatable manner with Michaelis--Menten constants of 27.7 microM and 257 microM respectively. On the other hand, hOAT1 and hOAT2 did not transport pravastatin. Gemfibrozil and its glucuronide and carboxylic metabolite forms inhibited the uptake of pravastatin by hOAT3 with IC(50) values of 6.8 microM, 19.7 microM and 5.4 microM, respectively. Considering the plasma concentrations of gemfibrozil and its metabolites in humans, the inhibition of hOAT3-mediated pravastatin transport by gemfibrozil and its metabolites would lead to a decrease in the renal clearance of pravastatin in clinical settings.
Subject(s)
Anticholesteremic Agents/metabolism , Anticholesteremic Agents/pharmacology , Gemfibrozil/pharmacology , Kidney/metabolism , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Pravastatin/metabolism , Animals , Anticholesteremic Agents/antagonists & inhibitors , Cell Line, Transformed , Dose-Response Relationship, Drug , Drug Antagonism , Gemfibrozil/antagonists & inhibitors , Humans , Kidney/cytology , Mice , Mice, Transgenic , Organic Anion Transporters, Sodium-Independent/genetics , Organic Anion Transporters, Sodium-Independent/metabolism , Pravastatin/antagonists & inhibitors , Pravastatin/pharmacologyABSTRACT
No disponible
Subject(s)
Male , Aged , Humans , Rhabdomyolysis/chemically induced , Pravastatin/adverse effects , Antibodies, Monoclonal/adverse effects , Pravastatin/antagonists & inhibitors , Drug Interactions , Creatine Kinase/blood , Creatine Kinase , Hyperlipidemias/drug therapyABSTRACT
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been developed as lipid-lowering drugs, and are well recognized to reduce morbidity and mortality from coronary artery disease. Several recent experimental studies have focused on the inhibitory effects of HMG-CoA reductase inhibitor on tumor cell growth in vitro and in vivo, dependent on a direct effect on cancer cells. In the present study, we aimed to investigate the potential anti-angiogenic effect of pravastatin and its mechanism of action. Using human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of pravastatin on the various steps of angiogenesis, including endothelial cell proliferation and adhesion to extracellular matrix proteins. Pravastatin induced a dose-dependent decrease in the proliferative activity of endothelial cells, which was dependent on the cell cycle arrest to the G1 phase and not on cell apoptosis. G1 arrest was due to the decrease of cyclin D, cyclin E and cyclin-dependent kinase 2 levels. In addition, pravastatin inhibited tube formation on Matrigel and adhesion to extracellular matrix, but did not affect matrix metalloproteinase production. The present results demonstrate the anti-angiogenic activity of pravastatin and its potential use as an anticancer drug is suggested.
Subject(s)
Endothelium, Vascular/cytology , G1 Phase/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Neovascularization, Pathologic/prevention & control , Pravastatin/pharmacology , Angiogenesis Inhibitors/pharmacology , Apoptosis/drug effects , Apoptosis/physiology , CDC2-CDC28 Kinases/drug effects , CDC2-CDC28 Kinases/genetics , CDC2-CDC28 Kinases/metabolism , Cell Division/drug effects , Cells, Cultured , Cyclin D , Cyclin E/drug effects , Cyclin E/genetics , Cyclin E/metabolism , Cyclin-Dependent Kinase 2 , Cyclins/drug effects , Cyclins/genetics , Cyclins/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Gene Expression/drug effects , Gene Expression/physiology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase 9/chemistry , Neovascularization, Pathologic/drug therapy , Polyisoprenyl Phosphates/pharmacology , Pravastatin/antagonists & inhibitors , Pravastatin/therapeutic use , Randomized Controlled Trials as Topic , Sesquiterpenes , Umbilical Veins/cytology , Umbilical Veins/drug effectsABSTRACT
Pravastatin has been shown, in an experimental model of ischemia reperfusion, to increase adenosine levels, which exert a potent and protective effect on the heart. The purpose of this study was to investigate whether pravastatin can provide cardioprotection by increased production of adenosine in patients undergoing coronary angioplasty, a clinical model of ischemia reperfusion. Thirty-five hyperlipidemic patients who underwent elective angioplasty for a major epicardial coronary artery were randomly allocated to either 3-month pravastatin or placebo before catheterization. In the placebo group, the mean ST-segment shift during the second balloon inflation was similar that observed during the first inflation, whereas in the preconditioned patients, the shift was significantly less, which is consistent with ischemic preconditioning. In the pravastatin-treated patients, the changes of ST-segment shift were similar between the first and second balloon inflations. In contrast, the patients who received aminophylline developed higher ST-segment shifts during the first and second inflations than those in the pravastatin-treated group alone. Measurements of chest pain score and myocardial lactate extraction ratios during inflation mirrored those of the ST-segment shift. The present study demonstrates that administration of pravastatin results in a significant gain in tolerance to ischemia during angioplasty. The effect of pravastatin was abolished by aminophylline, suggesting that the cardioprotective effect of pravastatin may result from activation of adenosine receptors.
Subject(s)
Adenosine/physiology , Angioplasty, Balloon, Coronary , Anticholesteremic Agents/therapeutic use , Coronary Disease/therapy , Hyperlipidemias/drug therapy , Pravastatin/therapeutic use , Aminophylline/pharmacology , Analysis of Variance , Anticholesteremic Agents/antagonists & inhibitors , Coronary Disease/complications , Electrocardiography , Female , Hemodynamics , Humans , Hyperlipidemias/complications , Lactates/blood , Male , Middle Aged , Myocardial Ischemia/diagnosis , Pravastatin/antagonists & inhibitorsABSTRACT
The objectives of this review are to discuss the role of cytochrome P450 (CYP450) isoforms in drug metabolism, to explain differences in metabolism among the HMG-CoA reductase inhibitors (HMGs, statins), to review drug-drug and drug-food interaction studies dealing with the HMGs, to present case reports dealing with HMG-related myopathy, to discuss major clinical implications of these case reports and to express an opinion of use of HMGs in clinical practice.
Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Enzyme Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypolipidemic Agents/pharmacology , Aged , Clinical Trials as Topic , Cytochrome P-450 Enzyme Inhibitors , Diltiazem/pharmacology , Drug Interactions , Female , Guidelines as Topic , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Isoenzymes/metabolism , Itraconazole/pharmacology , Lovastatin/antagonists & inhibitors , Lovastatin/pharmacology , Male , Middle Aged , Muscular Diseases/chemically induced , Pravastatin/antagonists & inhibitors , Rhabdomyolysis/chemically induced , Simvastatin/antagonists & inhibitors , Simvastatin/pharmacologyABSTRACT
Paraoxonase (PON) is an enzyme carried by high-density lipoprotein cholesterol (HDL-C). Two gene polymorphisms leading to amino acid substitutions of methionine for leucine at position 55 (M/L55) and arginine for glutamine at position 192 (R/Q192) modulate the activity of the enzyme and possibly also lipid and apolipoprotein concentrations. Our purpose was to examine the effect of the PON genotype on HDL-C and apolipoprotein AI (apo AI) responses to pravastatin treatment. Fifty-one mildly hypercholesterolemic male subjects (mean age 35 +/- 4 years) were enrolled by this prospective, randomized, double-blind study. Lipid concentrations were measured at baseline and after 6 months of pravastatin (n = 25) or placebo (n = 26) therapy. Low active (MM, ML or QQ) and high active (LL or RQ, RR) PON genotype groups were related to lipid and apolipoprotein concentration changes. Pravastatin increased the apo AI concentration 12% (P = 0.017, RANOVA) and tended to increase the HDL-C concentration (P = 0.095, RANOVA) in R allele carriers but not in QQ homozygotes. Significant predictors of the change in apo AI concentration during pravastatin treatment were R/Q192 genotype (P = 0.002), apo AI concentration at baseline (P = 0.002) and M/L55 genotype (P = 0.042). Correspondingly, R/Q192 (P = 0.009) and M/L55 (P = 0.050) genotypes were the statistically significant determinants of HDL-C concentration change. The PON genotype thus modifies the effect of pravastatin on serum HDL-C and apo AI concentrations. This could partly explain the contradictory results obtained from previous studies on the effects of statins on the serum HDL-C concentration.
Subject(s)
Cholesterol, HDL/blood , Esterases/genetics , Pravastatin/antagonists & inhibitors , Pravastatin/pharmacology , Adult , Anticholesteremic Agents/antagonists & inhibitors , Anticholesteremic Agents/pharmacology , Aryldialkylphosphatase , Double-Blind Method , Esterases/physiology , Genotype , Haplotypes/drug effects , Haplotypes/genetics , Humans , Male , Prospective StudiesABSTRACT
The transport mechanism of pravastatin, a new cholesterol-lowering drug, was compared in vitro with rat hepatocyte primary culture and mouse skin fibroblasts (L-cells). The uptake of 14C-labeled pravastatin by cultured hepatocytes was temperature- and dose-dependent. The temperature-dependent uptake as a function of [14C]pravastatin concentration showed saturation kinetics with Km = 32.2 microM and a maximal uptake rate of 68 pmol/mg protein/min. The uptake of pravastatin was inhibited significantly by metabolic inhibitors such as rotenone, oligomycin A, antimycin A, 2,4-dinitrophenol and KCN. Unlabeled pravastatin as well as R-416 and R-195, structural analogues of pravastatin, effectively competed for the hepatic uptake of [14C]pravastatin at 37 degrees. These results indicate that pravastatin is taken up by the liver by an active transport. In contrast, the transport of pravastatin by L-cells was temperature-independent and non-saturable, suggesting that the uptake of pravastatin by L-cells is mediated by passive diffusion. The marked difference in the uptake mechanism of pravastatin between hepatocytes and L-cells may account for a unique feature of this drug in that the uptake and inhibition of cholesterol biosynthesis occur selectively in the liver.
