Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 73 No. 3 pp. 579ñ588, 2016 ISSN 0001-6837 Polish Pharmaceutical Society CORONARY EFFECT OF FIBRATES ON PROTEINS AND ENZYMES WHICH HYDROLYZE TRIACYLGLYCEROLS RENATA FRANCIK 1,2*, JADWIGA KRYCZYK 3 and S£AWOMIR FRANCIK 4 1 Department of Bioorganic Chemistry, 2 Department of Food Chemistry and Nutrition, Jagiellonian University, Medical College, Faculty of Pharmacy, 9 Medyczna St., 30-688 KrakÛw, Poland 2 Institute of Health, State Higher Vocational School, 1 Staszica St., 33-300 Nowy Sπcz, Poland 3 Jagiellonian University Medical College, Department of Food Chemistry and Nutrition, 9 Medyczna St., 30-688 KrakÛw, Poland 4 Department of Mechanical Engineering and Agrophysics, University of Agriculture in Krakow, Faculty of Production Engineering and Energetics, 116 B Balicka St., 30-149, KrakÛw, Poland Abstract: Clofibric acid derivatives called fibrates, are quite commonly used lipid-lowering drugs, so it is nec- essary to know beneficial and adverse effects of these compounds on the body. The European Medicines Agencyís Committee for Medicinal Products for Human Use (CHMP) has concluded that benefits of four fibrates such as: bezafibrate, ciprofibrate, fenofibrate and gemfibrozil continue outweigh their risk in treatment of people with blood lipid disorders. According to recommendations of the CHMP fibrates should not be used as first-line drugs, except in patients with severe hypertriglyceridemia and patients who cannot use statins. In this paper, we focused on effect of clofibric acid derivatives on lipid metabolism, in particular on apo proteins and regulatory enzymes. Keywords: clofibric acid derivatives, apo proteins, regulatory enzymes, lipid metabolism Abbreviations: BF ñ bezafibrate, CE ñ cholesterol esters, CF ñ ciprofibrate, FC ñ free cholesterol, FF ñ fenofi- brate, GF ñ gemfibrozil, HDL ñ high density lipoproteins, HL ñ hepatic lipase (EC 3.1.1.3), IDL ñ intermedi- ate density lipoproteins, KF ñ clofibrate, LCAT ñ lecithin-cholesterol acyltransferase (EC2.3.1.43), LDL ñ low density lipoproteins, LDLR ñ low-density lipoprotein receptor, LPL ñ lipoprotein lipase (EC3.1.1.34), LRP ñ LDL receptor-related protein, PL ñ phospholipids, PPAR ñ peroxisome proliferator activated receptor, RAP ñ receptor-associated protein, SR-B1 ñ scavenger receptor class B, SREBP 1c ñ sterol regulatory element bind- ing protein 1c, VLDL ñ very low density lipoproteins Among many compounds that affect change in fatty acids taken with food. TG constitute lipid concentration of TG (triglycerides) in plasma are material in white adipose tissue (90% of lipid con- selected clofibric acid derivatives. These com- tent) as well as reserve and energy materials. pounds modify concentration of structural and enzy- In humans, there are lipoprotein fractions such matic proteins both in plasma, cytoplasm, and other as chylomicrons, very low density lipoprotein organelles, such as mitochondria or peroxisomes. (VLDL), low density lipoprotein (LDL) and high- Elevated concentrations of TG in plasma entails density lipoprotein (HDL). TG- rich are VLDL and serious health consequences as a development of chylomicrons. TG hydrolysis occurs with simultane- atherosclerosis, and therefore coronary heart disease ous degradation of these fractions and is prerequisite and ischemic heart disease. In contrast, clofibric for proper lipid metabolism because it provides fatty acid derivatives are among very few therapeutic acids to all tissues and organs. This process depends agents lowering TG levels by affecting structural on activities of many proteins including apolipopro- and regulatory proteins of lipoprotein fraction as teins (apo). In conditions when amount of TG frac- well as enzymatic and receptor proteins. tions in plasma is increased, are used lipid-lowering TG are esters of glycerol and higher fatty acids. drugs. In the body, TG are formed in liver, intestine and in adipose tissue. Then, triglycerides are bound in Fibrates as clofibric acid derivatives lipoprotein fractions, which move to plasma. In the Clofibric acid derivatives called fibrates, are body, as a TG are transported most of the long chain quite commonly used lipid-lowering drugs, so it is * Corresponding author: e-mail: [email protected]; phone: +48126205507, fax: +48126205405 579 580 RENATA FRANCIK et al. necessary to know adverse effects of these com- in patients with severe hypertriglyceridemia and pounds on the body. The European Medicines patients who cannot use statins. Agencyís Committee for Medicinal Products for Clofibric acid derivatives impact on hepato- Human Use (CHMP) has concluded that benefits of cytes in different organelles, especially in nucleus, four fibrates such as: bezafibrate, ciprofibrate, mitochondrions and peroxisomes (Fig. 1). Most fenofibrate and gemfibrozil continue outweigh their studies relating to the effect of clofibric acid deriva- risk in treatment of people with blood lipid disor- tives were performed in order to determine their ders. According to recommendations of the CHMP, impact on the activity of peroxisomal enzymes (1- fibrates should not be used as first-line drugs, except 3). For example, in studies conducted on rats it was Figure 1. Half structural formulas of clofibric acid, clofibrate, and fenofibrate, bezafibrate, ciprofibrate, simfibrate and gemfibrozil (accord- ing to the IUPAC systematic name). Coronary effect of fibrates on proteins and enzymes which hydrolyze triacylglycerols 581 Table 1. Pharmacokinetics and metabolism of selected clofibric acid derivatives. Degree of Half-life Fibrates Excretion protein binding [%] [h] Fenofibrate > 99 19ñ27* 100% renal as glucuronides form Clofibrate 96 18ñ22** 100% renal as metabolized form Bezafibrate 95 1.5ñ3.0*** 100% renal as unchanged form Gemfibrozil 98 1.1ñ3,7**** 100% renal as metabolized and glucuronides form Ciprofibrate 99 70ñ81***** 100% renal as glucuronides form * The values are based on the publications: *(11, 13), **(12, 13), ***(13), ****(13, 58, 59), *****(60). demonstrated that clofibric acid derivatives cause results in improved absorption compared to a stan- significant hypertrophy of peroxisome in liver tissue dard substance. It increases about 30% bioavailabili- (4, 5). In turn, in humans, it is assumed that peroxi- ty of drug. Fibrates are very well absorbed into blood some hypertrophy under the influence of clofibrate from gastrointestinal tract. In blood, about 95% of occurs only to a limited extent (6). Clofibrate in fibrates are bound to plasma albumin. BF, CF and patients increases amount of liver mitochondrions GF reach maximum concentration after 2 h while FF (7). In consequence, it leads to increase of acetyl- after 4-6 h. The metabolism of these compounds CoA which is involved in Krebs cycle. takes place in the liver whereas they are excreted in 60-90% by kidney. Biological half-life of FF is equal Structure and mechanism of effects of clofibric to 22 h; BF - 2 h; CF - 18 h and GF - 1.1 h (Table 1). acid derivatives Fenofibrate is well absorbed after oral admin- Clofibrate (KF) was the first one to be used in istration, with peak plasma levels attained in 6 to 8 the early sixties (1967, in the U.S.) but then, due to hours. It is insoluble in aqueous media suitable for numerous side effects, it was withdrawn from use injection. It creates a metabolite - fenofibric acid, (8). Successively, fenofibrate (FF), bezafibrate (BF), which has a half life of about 20 hours (11). ciprofibrate (CF) and gemfibrozil (GF) were put on Bezafibrate in serum half life of a single 20 mg/kg the market in the seventies. Fibrates are halogen oral dose in monkeys was 2-3 hours. This is compa- derivatives and contain chlorine atom (excluding rable to t1/2 in man. Tissue distribution studies in ani- gemfibrozil). Their chemical structure refers to short mals found the highest bezafibrate concentration in chain fatty acids. In molecules of KF, FF and BF the liver and intestine 8 hours after oral dosing. one of substituents is chlorine connected by covalent Serum protein binding ranges from 88.4 to 93.5% bond to aromatic ring. It affects biological function after 0.5 to 8 hours, respectively. Male and female of clofibric acid derivatives. Replacement of chlo- beagle dogs receiving oral bezafibrate at 30 mg/kg rine atom in the molecule of clofibirc acid with had t1/2 = 3 and 2.7 hours (12, 13). extensive substituent such as 4-chlorobenzoyl in Half-life CF in normal volunteers averages case of FF, or 2-(4-chlorobenzamide)-ethyl in case 18 to 22 hours (range 14 to 35 hours) but can vary of BF increased lipophilicity of these compounds (9, by up to 7 hours in the same subject at different 10). times (13). Drugs with pharmacological properties similar Fibrates have been used in treatment of to FF and BF are: CF - (2-[4-(2,2-dichlorocyclo- endogenous hypertriglyceridemia, mixed hyperlipi- propyl)-phenoxy]-2-methylpropanoic acid) and sim- demia, chylomicronemia syndrome, hypercholes- fibrate - (2-(4-chlorophenoxy)-2-methylpropanoic terolemia or polymetabolic syndrome which acid 1,3-propanediyl ester). Gemfibrozil - 5-(2,5- includes hyperinsulinemia, diabetes type II, hyper- dimethylphenoxy)-2,2-dimethyl-pentanoic acid) is tension and obesity. These disorders occur with another drug belonging to clofibric acid derivatives. coronary heart disease, ischemic heart disease, or This compound is ω-hydroxyvaleric acid derivative diabetes type II (11, 12). Clofibric acid derivatives connected by ester bond with dimethylphenyl group are well tolerated drugs