Naslov
Antilipidemic Drugs - Biotransformation and Fate in the Body

Autori
Jadrijević-Mladar Takač, Milena

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, pregledni

Izvornik
CROPBSA-CEEPUS Summer University on Atherosclerosis Program and Book of Abstracts / Juretić, Dubravka - Zagreb : Farmaceutsko-biokemijski fakultet Sveučilišta u Zagrebu, 2003, 3-4

Skup
CROPBSA-CEEPUS Summer University on Atherosclerosis

Mjesto i datum
Zadar, Hrvatska, 23.07.2003. - 30.07.2003

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Antilipidemic drugs; Hyperlipidemia; Lipid-lowering agents; Biotransformation

Sažetak
Drugs that affect blood lipids (Antilipidemic drugs, Lipid-lowering agents, and Anti-hyperlipidemic agents) may be classified as cardiovascular drugs because of the relation of blood lipids to atherosclerosis. Atherosclerosis can be a disorder in lipid metabolism or a normal effect of a diet high in certain lipids. The etiology of atherosclerosis, one of the most significant diseases of our time has not yet been elucidated. However, increased lipid blood levels, particularly cholesterol levels are clearly an important risk factor for the disease, since one of the major lipids in the atheroma is cholesterol. There is correlation between blood cholesterol content and the incidence of coronary occlusion. The blood-beta-lipoprotein and serum trigliceride levels also correlate somewhat with the incidence of coronary occlusion and with type of fat in the diet. A rational approach for decreasing the risk of atherosclerosis and possibly treating some aspects of the disease (heart attack, cerebral and peripheral vascular dysfunction) is to lower the blood lipid levels. Drugs that affect blood lipids can be classified as it follows: A) Compounds that lower trigliceride and cholesterol blood levels &middot ; Aryloxyalkane carbonic acid derivatives (clofibrate, etofibrate, etofylline clofibrate, benzafibrate, fenofibrate, gemfibrozil, &#8230 ; ) &middot ; Nicitinic acid and analogs (5-fluoronicotinic acid, acipimox, &#8230 ; ) B) Compounds that mainly lower cholesterol levels &middot ; Anion exchange resins (colestiramine) &middot ; Inhibitors of HMG-CoA reductase inhibitors - statins (lovastatin, simvastatin, pravastatin, &#8230 ; ) &middot ; Probucol &middot ; Dextrothyroxine &middot ; Sitosterol Many of these drugs are in the form of their prodrugs, e.g. lovastatin, simvastatin or prodrugs of clofibric acid. Clofibrate and clofibric acid derivative type of drugs, are rapidly and completely absorbed and metabolized presystematically to clofibric acid, which is mainly bound to albumin in plasma, and excreted via the kidney in the form of glucuronides. Although the mechanism of action is still not completely understood, it is known that clofibrate increases the activity of lipoprotein lipase. Gemfibrozil is extensively metabolized in humans. Unchanged drug in urine accounts for only 5% of the dose. Conjugation of gemfibrozil to form an ester glucuronide and phase I oxidation of gemfibrozil to form phenolic, benzylic alcohol, and benzoic acid metabolites represent the major biotransformation products in humans. Nicotinic acid dose-dependently lowers the concentration of free fatty acids as well as triglicerides and cholesterol. After oral administration, completely absorbed acid is metabolized in the liver and conjugates with glycine to nicotinuric acid. Acipimox, which is chemically related to nicotinic acid and has similar effect and side effects, is almost completely eliminates unchanged via the kidneys. Statins (or vastins) represent a new class of lipid-lowering compounds that inhibit HMG-CoA reductase, the first limiting and rate-limiting step in cholesterol biosynthesis in cells. Statins are generally more effective than probucol, bile acid sequestrants, and fibrates at lowering total and LDL cholesterol. These drugs now represent the major class of compounds for monotherapy treatment of patients with Types IIa and IIb hypercholesterolemie. Whereas pravastatin (pravastatin sodium) is given as the active hydroxy acid, the remaining statins are given as prodrug lactone forms, which are enzymatically converted by serum or tissue esterases to the corresponding hydroxy acid. These hydrolysis products inhibit HMG-CoA reductase activity. Lovastatin and simvastatin are extensively biotransformed in vivo and in vitro. The prodrug statins also undergo reversible equilibrium between the lactone and open chain hydroxy acid forms in vivo, and statin metabolites are mainly eliminated into bile. Phase I metabolites of statins include 6&#8217 ; - and 3&#8217 ; -hydroxy derivatives as major metabolites in vivo. 6&#8217 ; -hydroxy derivatives undergo rapid nonenzymatic conversion to corresponding 3&#8217 ; -hydroxy derivatives under acidic condition. Both lactone and hydroxy acid forms of prodrug statin metabolites accumulate in tissue, in vivo. A large number of statin metabolites arising from oxidation, hydration, conjugation, and isomerization reactions have been identified. Statins are particularly attractive agents for the acute and long-term treatment of cardiovascular diseases because they target multiple pathways that ultimately converge in atherothrombotic events. The use of statins in the treatment of lipid-related disorders is therefore expected to rise. Generally, statins have a benign side-effect profile and are well tolerated. The most serious adverse effect arises from cell damage in liver and skeletal muscle. The incidence of myopathies is low, but the increasing use of statins implies that more physicians will encounter this clinical entity. 1. S. K. Baker and M. A. Tarnopolsky, Statin myopathies: pathophysiologic and clinical perspectives, Clin. Invest. Med. 24 (2001) 258-272. 2. I. Ahnfelt-R&oslash ; nne, Enzymes and enzyme inhibitors, in Textbook of drug design and development, 2nd Ed. (P. Krogsgaard-Larsen et all. Ed.), Harwood Academic Publishers, Amsterdam, 1996, 289-326. 3. W. O. Foye, T. L. Lemke and D. A. Williams, Principles of medicinal chemistry, 4th Ed., Lippincott Williams & Wilkins, Philadelphia, 1995, 499-534. 4. L. K. Low and N. Castagnoli, Jr., Metabolic changes of drugs and related organic compunds, in Wilson and Gisvold&#8217 ; s textbook of organic medicinal and pharmaceutical chemistry, 8th Ed. (R. F. Doerge, Ed.), J. B. Lippincott Com., 1982, 55-127.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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