Drugs online research references
Biol Pharm Bull. 1998 Nov;21(11):1142-7.
Comparison of the effects of gemfibrozil and clofibric acid on peroxisomal enzymes and cholesterol synthesis of rat hepatocytes.
Hashimoto F, Taira S, Hayashi H.
Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan.
We studied whether the peroxisomal proliferation, induction of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and activation of cholesterol synthesis by gemfibrozil shown in whole body (Hashimoto F., Ishikawa T., Hamada S. and Hayashi H., Biochemical. Pharm., 49, 1213-1221 (1995)) is also detected at a culture cell level, and we made a comparative analysis of the effects of clofibric acid. Gemfibrozil at 0.25 mM increased the activity of some peroxisomal enzymes (catalase and the cyanide-insensitive fatty acyl-CoA oxidizing system) after incubation for 72 h. However, contrary to whole body experiments, gemfibrozil decreased the activity of HMG-CoA reductase and cholesterol synthesis from [14C]acetate. At 1 mM, gemfibrozil decreased not only the activity of HMG-CoA reductase and cholesterol synthesis, but also the protein content of the cells and peroxisomal enzyme activity, indicating nonspecific inhibition at this concentration. Clofibric acid (0.25 and 1 mM) increased the activity of peroxisomal enzymes, but decreased the activity of HMG-CoA reductase and cholesterol synthesis. With respect to the direct effect on HMG-CoA reductase in the cell homogenate, gemfibrozil at 0.25 mm did not affect the activity, but it clearly inhibited the activity at 2 mM and above. Clofibric acid at 2 mM hardly affected the activity, but it clearly decreased the activity at 5 mM and over. That is, gemfibrozil directly inhibited the activity more strongly than clofibric acid. The direct inhibition of the enzyme itself required higher concentrations of both agents than did inhibition at the culture cell level. These results suggest that the cytotoxicity of gemfibrozil is greater than that of clofibric acid, and that gemfibrozil, as well as clofibric acid, can induce peroxisomal enzymes in the culture cell level. In contrast to whole body results, gemfibrozil may suppress cholesterol synthesis from [14C]acetate through the inhibition of HMG-CoA reductase at the culture cell level. The decreases in the reductase activity caused by gemfibrozil and clofibric acid at the culture cell level may not be caused by the direct inhibition of the enzyme.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9853402&dopt=Abstract
Yao Xue Xue Bao. 1996;31(10):737-41.
[Two-site absorption model fits to pharmacokinetic data of gemfibrozil in man]
[Article in Chinese]
Liu XD, Xie L, Wang J, Zhou YS, Wang Z, Liu GQ.
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing.
The plasma concentration-time data of gemfibrozil in 8 male subjects were determined after an oral dose of 600 mg. Two-peak concentrations in plasma were observed. A kind of one-compartment model with two-sites of drug absorption was proposed and used to fit these data. A good agreement between observed and predicted data was found in all subjects with correlation indexes (gamma 2) > 0.99. The corresponding pharmacokinetic parameters were estimated as follows: Tmax1, 1.10 +/- 0.46 h; Tmax2, 2.60 +/- 0.73 h; Cmax1, 13.62 +/- 4.30 micrograms.ml-1; Cmax2, 17.22 +/- 3.83 micrograms.ml-1; T1, 0.06 +/- 0.06 h; T2, 1.42 +/- 0.57 h and T3, 1.79 +/- 0.60 h.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9863240&dopt=Abstract
Thromb Haemost. 1998 Dec;80(6):942-8.
Fibrate-modulated expression of fibrinogen, plasminogen activator inhibitor-1 and apolipoprotein A-I in cultured cynomolgus monkey hepatocytes -- role of the peroxisome proliferator-activated receptor-alpha.
Kockx M, Princen HM, Kooistra T.
Gaubius Laboratory, TNO-PG, Leiden, The Netherlands.
Fibrates are used to lower plasma triglycerides and cholesterol levels in hyperlipidemic patients. In addition, fibrates have been found to alter the plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein A-I (apo A-I). We have investigated the in vitro effects of fibrates on fibrinogen, PAI-1 and apo A-I synthesis and the underlying regulatory mechanisms in primary monkey hepatocytes. We show that fibrates time- and dose-dependently increase fibrinogen and apo A-I expression and decrease PAI-1 expression in cultured cynomolgus monkey hepatocytes, the effects demonstrating different potency for different fibrates. After three consecutive periods of 24 h the most effective fibrate. ciprofibrate (at 1 mmol/l), increased fibrinogen and apo A-I synthesis to 356% and 322% of control levels, respectively. Maximum inhibition of PAI-1 synthesis was about 50% of control levels and was reached by 1 mmol/l gemfibrozil or ciprofibrate after 48 h. A ligand for the retinoid-X-receptor (RXR), 9-cis retinoic acid, and specific activators of the peroxisome proliferator-activated receptor-alpha (PPARalpha), Wy14,643 and ETYA, influenced fibrinogen, PAI-1 and apo A-I expression in a similar fashion, suggesting a role for the PPARalpha/RXRalpha heterodimer in the regulation of these genes. When comparing the effects of the various compounds on PPARalpha transactivation activity as determined in a PPARalpha-sensitive reporter gene system and the ability of the compounds to affect fibrinogen, PAI-1 and apo A-I antigen production, a good correlation (r=0.80; p <0.01) between PPARalpha transactivation and fibrinogen expression was found. Apo A-I expression correlated only weakly with PPARalpha transactivation activity (r=0.47; p=0.24), whereas such a correlation was absent for PAI-1 (r=0.03; p=0.95). These results strongly suggest an involvement of PPARalpha in the regulation of fibrinogen gene expression.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9869165&dopt=Abstract
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