関: clofibrate、clofibric acid

WordNet

a drug (trade name Atromid-S) that reduces lipids in the blood serum; used to treat some cardiovascular diseases (同)Atromid-S

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/10/07 15:58:50」(JST)

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Clofibrate

Gemfibrozil

Etofibrate

Aluminium clofibrate

In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), and are therefore hypolipidemic agents.

Members

Fibrates prescribed commonly are:

Bezafibrate (e.g. Bezalip)
Ciprofibrate (e.g. Modalim)
Clofibrate (largely obsolete due to side-effect profile, e.g. gallstones)
Gemfibrozil (e.g. Lopid)
Fenofibrate (e.g. TriCor)
Clinofibrate (e.g. Lipoclin)

Indications

Fibrates are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins.^[1] Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non-fatal heart attacks, but do not improve all-cause mortality and are therefore indicated only in those not tolerant to statins.^[2]^[3]

Although less effective in lowering LDL and triglyceride levels by increasing HDL levels and decreasing triglyceride levels, they seem to reduce insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes mellitus type 2).^[4] They are therefore used in many hyperlipidemias. Fibrates are not suitable for patients with low HDL levels. As per US FDA label change of trichor, it is recommended that the HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline. Fibrate therapy should not be re-initiated Medwatch

Mechanisms of action

Evidence from studies in rodents and in humans is available to indicate five major mechanisms underlying the above-mentioned modulation of lipoprotein phenotypes by fibrates:^[5]

Induction of lipoprotein lipolysis: Increased triglyceride-rich lipoprotein (TRL) lipolysis could be a reflection of changes in intrinsic lipoprotein lipase (LPL) activity or increased accessibility of TRLs for lipolysis by LPL owing to a reduction of TRL apoC-III content.
Induction of hepatic fatty acid (FA) uptake and reduction of hepatic triglyceride production: In rodents, fibrates increase FA uptake and conversion to acyl-CoA by the liver owing to the induction of FA transporter protein and acyl-CoA synthetase activity. Induction of the ß-oxidation pathway with a concomitant decrease in FA synthesis by fibrates results in a lower availability of FAs for triglyceride synthesis, a process that is amplified by the inhibition of hormone-sensitive lipase in adipose tissue by fibrates.
Increased removal of LDL particles: Fibrate treatment results in the formation of LDL with a higher affinity for the LDL receptor, which are thus catabolized more rapidly.
Reduction in neutral lipid (cholesteryl ester and triglyceride) exchange between VLDL and HDL may result from decreased plasma levels of TRL.
Increase in HDL production and stimulation of reverse cholesterol transport: Fibrates increase the production of apoA-I and apoA-II in liver, which may contribute to the increase of plasma HDL concentrations and a more efficient reverse cholesterol transport.

Side effects

Most fibrates can cause mild stomach upset and myopathy (muscle pain with CPK elevations). Since fibrates increase the cholesterol content of bile, they increase the risk for gallstones.

In combination with statin drugs, fibrates cause an increased risk of rhabdomyolysis, idiosyncratic destruction of muscle tissue, leading to renal failure. A powerful statin drug, cerivastatin (Lipobay), was withdrawn because of this complication. The less lipophilic statins are less prone to cause this reaction, and are probably safer when combined with fibrates.

Drug toxicity includes acute kidney injury.^[6]

Pharmacology

PPAR

Although used clinically since the 1930s,^[7] if not earlier, the mechanism of action of fibrates remained unelucidated until, in the 1990s, it was discovered that fibrates activate PPAR (peroxisome proliferator-activated receptors), especially PPARα. The PPARs are a class of intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation.

Activating PPARs induces the transcription of a number of genes that facilitate lipid metabolism.

Fibrates are structurally and pharmacologically related to the thiazolidinediones, a novel class of anti-diabetic drugs that also act on PPARs (more specifically PPARγ)

Fibrates are a substrate of (metabolized by) CYP3A4.^[8]

Fibrates have been shown to extend lifespan in the roundworm C. elegans. ^[9]

References

^ Steiner G (December 2007). "Atherosclerosis in type 2 diabetes: a role for fibrate therapy?". Diab Vasc Dis Res 4 (4): 368–74. doi:10.3132/dvdr.2007.067. PMID 18158710.
^ Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P, Pilote L, Genest J, Eisenberg MJ (2009). "Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review". Am J Med 122 (10): 962.e1–962.e8. doi:10.1016/j.amjmed.2009.03.030. PMID 19698935.
^ Jun M, Foote C, Lv J, et al. (2010). "Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis". Lancet 375 (9729): 1875–1884. doi:10.1016/S0140-6736(10)60656-3.
^ Wysocki J1, Belowski D, Kalina M, Kochanski L, Okopien B, Kalina Z (2004). "Effects of micronized fenofibrate on insulin resistance in patients with metabolic syndrome". INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS 42 (4): 212–217. PMID 15124979.
^ Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC (1998). "Mechanism of action of fibrates on lipid and lipoprotein metabolism". Circulation 98 (19): 2088–93. PMID 9808609.
^ Zhao YY, Weir MA, Manno M, Cordy P, Gomes T, Hackam DG, et al. (2012). "New fibrate use and acute renal outcomes in elderly adults: a population-based study.". Ann Intern Med 156 (8): 560–9. doi:10.1059/0003-4819-156-8-201204170-00003. PMID 22508733.
^ "Pharmaceutical composition and method for treatment of digestive disorders - Patent 4976970". Retrieved 2008-12-20.
^ http://www.stacommunications.com/journals/cardiology/2004/June/Pdf/034.pdf
^ http://www.impactaging.com/papers/v5/n4/full/100548.html

UpToDate Contents

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1. フィブラート系薬剤による脂質低下 lipid lowering with fibric acid derivatives
2. 高トリグリセリド血症患者に対するアプローチ approach to the patient with hypertriglyceridemia
3. スタチン系およびフィブラート系以外の薬剤による脂質低下 lipid lowering with drugs other than statins and fibrates
4. スタチン誘発性ミオパチー statin myopathy
5. Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis)

English Journal

Ketogenic response to cotreatment with bezafibrate and medium chain triacylglycerols in healthy humans.

Courchesne-Loyer A1, St-Pierre V2, Hennebelle M2, Castellano CA3, Fortier M3, Tessier D2, Cunnane SC2.
Nutrition (Burbank, Los Angeles County, Calif.).Nutrition.2015 Oct;31(10):1255-9. doi: 10.1016/j.nut.2015.05.015. Epub 2015 Jun 6.
OBJECTIVES: The aim of this study was to compare the ketogenic effect of the peroxisome proliferator-activated receptor-α stimulator, bezafibrate (BEZA), alone or in combination with medium-chain triacylglycerols (MCTs) in healthy adults.METHODS: Eighteen healthy adults completed the study: 10 were
PMID 26333891

Safety considerations with fenofibrate/simvastatin combination.

Filippatos TD1, Elisaf MS.
Expert opinion on drug safety.Expert Opin Drug Saf.2015 Sep;14(9):1481-93. doi: 10.1517/14740338.2015.1056778. Epub 2015 Jul 3.
INTRODUCTION: Fenofibrate/simvastatin combination is useful for patients with mixed dyslipidemia. Aim of this review is to critically present the safety aspects of the fenofibrate/simvastatin combination.AREAS COVERED: Current evidence regarding the adverse effects of fenofibrate/simvastatin combina
PMID 26134595

Fibrates protect against vascular endothelial dysfunction induced by paclitaxel and carboplatin chemotherapy for cancer patients: a pilot study.

Watanabe A1, Tanabe A, Maruoka R, Nakamura K, Hatta K, Ono YJ, Terai Y, Ohmichi M.
International journal of clinical oncology.Int J Clin Oncol.2015 Aug;20(4):829-38. doi: 10.1007/s10147-014-0779-y. Epub 2014 Dec 26.
BACKGROUND: Although we previously demonstrated that paclitaxel and carboplatin chemotherapy (TCchem) is associated with vascular toxicities, the underlying mechanisms remain unclear. Cisplatin is known to inhibit PPARα following microvascular damage to the kidneys. The primary aim of this study wa
PMID 25539886

Japanese Journal

Fibrate剤使用の臨床的意義 (特集脂質異常症診療のエビデンスと将来展望) -- (脂質異常症の治療薬--エビデンスと選択基凖)

横山信治
綜合臨床 60(7), 1530-1539, 2011-07
NAID 40018908306

Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: Results from a crossover study

Noguchi Tohru,Kobayashi Junji,Yagi Kunimasa,Nohara Atsushi,Yamaaki Naoto,Sugihara Masako,Ito Naoko,Oka Rie,Kawashiri Masaaki,Tada Hayato,Takata Mutsuko,Inazu Akihiro,Yamagishi Masakazu,Mabuchi Hiroshi
Atherosclerosis 217 (1), pp. 165-170 217(1), 165-170, 2011-07
… Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. … The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates. …
NAID 120003141452

Related Pictures

★リンクテーブル★

リンク元	「フィブラート」「フィブラート系薬剤」「clofibric acid」「フィブレート」
拡張検索	「clinofibrate」「simfibrate」「clofibrate」
関連記事	「fibrates」

「フィブラート」

Fibrates
	Drug class
	Fenofibrate, one of the most popular fibrates
Use	hypercholesterolemia and hypertriglyceridemia
Biological target	PPAR
External links
WebMD	medicinenet

　　[★]

英: fibrate
関: フィブラート系薬物、高脂血症治療薬

fibric acidの誘導体(fibric acid derivatves)

PPAR activators
HDL↑、LDL↓
peroxisome proliferator activated receptor(PPAR)を介して薬理作用を発現←転写因子
PPARα：肝臓、褐色脂肪細胞で発現。腎臓、心臓、骨格筋でやや発現 (GOO.957)

作用：(1)脂肪酸酸化、LPL合成↑、apoC-III↓ (GOO.957)

apoC-IIIは肝臓分解やレセプターを介した(LDLなどの)取り込みのinhibitorとして機能 (GOO.957)

HDL-Cの増加はapoA-IとApoA-IIの発現を刺激することによる (GOO.957)