Clofibrate: Difference between revisions

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{{drugbox
{{Drugbox
| IUPAC_name       = ethyl 2-(4-chlorophenoxy)-2-methylpropanoate
| Watchedfields = changed
| image             = Clofibrate.svg
| verifiedrevid = 443529702
| CAS_number        = 637-07-0
| IUPAC_name = ethyl 2-(4-chlorophenoxy)-2-methylpropanoate
| ATC_prefix        = C10
| image = Clofibrate.svg
| ATC_suffix        = AB01
 
| PubChem          = 2796
<!--Clinical data-->
| DrugBank          = APRD00879
| tradename =
| C=12|H=15|Cl=1|O=3
| Drugs.com = {{drugs.com|CONS|clofibrate}}
| molecular_weight  = 242.698 g/mol
| pregnancy_AU = B1
| bioavailability  =
| pregnancy_US = C
| protein_bound    = Variable, 92–97% at therapeutic concentrations
| pregnancy_category =   
| metabolism        = [[Hydrolysis|Hydrolyzed]] to clofibric acid; [[liver|hepatic]] [[glucuronidation]]
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| elimination_half-life = Highly variable; average 18–22 hours. Prolonged in [[renal failure]]
| legal_CA = <!--            / Schedule I, II, III, IV, V, VI, VII, VIII -->
| excretion        = [[Kidney|Renal]], 95 to 99%
| legal_UK = <!-- GSL        / P      / POM / CD / Class A, B, C -->
| pregnancy_AU     = B1
| legal_US = Discontinued
| pregnancy_US     = C
| legal_status =
| pregnancy_category=   
| legal_AU         = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA         = <!--            / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK         = <!-- GSL        / P      / POM / CD / Atromid-S Capsules (clofibrate capsules) is ethyl 2-(p-chlorophenoxy)-2-methyl-propionate, an antilipidemic agent.
Its molecular formula is C 12 H 15 O 3 Cl, molecular weight 242.7, and boiling point 148-150°C at 25 mm Hg. It is a stable, colorless to pale-yellow liquid with a faint odor and characteristic taste, soluble in common solvents but not in water. Each Atromid-S Capsule contains 500 mg clofibrate for oral administration
Class A, B, C -->
| legal_US         = Rx-only
| legal_status     =  
| routes_of_administration = Oral
| routes_of_administration = Oral
}}
{{SI}}


{{CMG}} 
<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = Variable, 92–97% at therapeutic concentrations
| metabolism = [[Hydrolysis|Hydrolyzed]] to [[clofibric acid]]; [[liver|hepatic]] [[glucuronidation]]
| elimination_half-life = Highly variable; average 18–22 hours. Prolonged in [[renal failure]]
| excretion = [[Kidney|Renal]], 95 to 99%


'''Associate Editor:''' {{CZ}}
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number = 637-07-0
| ATC_prefix = C10
| ATC_suffix = AB01
| PubChem = 2796
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00636
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2694
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = HPN91K7FU3
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00279
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 3750
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 565


<!--Chemical data-->
| C=12 | H=15 | Cl=1 | O=3
| molecular_weight = 242.698 g/mol
| smiles = Clc1ccc(OC(C(=O)OCC)(C)C)cc1
| InChI = 1/C12H15ClO3/c1-4-15-11(14)12(2,3)16-10-7-5-9(13)6-8-10/h5-8H,4H2,1-3H3
| InChIKey = KNHUKKLJHYUCFP-UHFFFAOYAE
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C12H15ClO3/c1-4-15-11(14)12(2,3)16-10-7-5-9(13)6-8-10/h5-8H,4H2,1-3H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KNHUKKLJHYUCFP-UHFFFAOYSA-N
| boiling_point = 148
}}
'''Clofibrate''' (tradename '''Atromid-S''') is an [[organic compound]].  It is marketed as a [[fibrate]]. It is a lipid-lowering agent used for controlling the high cholesterol and [[triacylglyceride]] level in the blood. It increases [[lipoprotein lipase]] activity to promote the conversion of [[VLDL]] to [[LDL]], and hence reduce the level of VLDL. It can increase the level of [[High Density Lipoprotein|HDL]] as well.


==Complications and controversies==
It can induce [[syndrome of inappropriate antidiuretic hormone hypersecretion|SIADH]], syndrome of inappropriate secretion of [[vasopressin|antidiuretic hormone ADH]] (vasopressin).


==[[Clofibrate (patient information)|For patient information, click here]]==
The [[World Health Organization]] Cooperative Trial on Primary Prevention of [[Ischaemic Heart Disease]] using clofibrate to lower serum [[cholesterol]] observed excess mortality in the clofibrate-treated group despite successful cholesterol lowering (47% more deaths during treatment with clofibrate and 5% after treatment with clofibrate) than the non-treated high cholesterol group. These deaths were due to a wide variety of causes other than heart disease, and remain "unexplained".<ref>{{cite journal |author= |title=WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the Committee of Principal Investigators |journal=Lancet |volume=2 |issue=8403 |pages=600–4 |date=September 1984 |pmid=6147641 |doi= |url=}}</ref>


==Overview==
Clofibrate was discontinued in 2002 due to adverse affects.


'''Clofibrate''' is a [[fibrate]].  It is used in the treatment of cardiovascular disease.
==Synthesis==
 
[[File:Clofibrate synthesis.svg|thumb||center|700px|Clofibrate synthesis.<ref>http://drugsynthesis.blogspot.co.uk/2012/04/laboratory-synthesis-of-clofibrate.html</ref>]]
==Generic Available==
 
Yes
 
==Use==
 
Adjunct to dietary therapy in the management of hyperlipidemias associated with high triglyceride levels (types III, IV, V); primarily lowers triglycerides and very low density lipoprotein
 
==Pregnancy Risk Factor==
C
 
==Lactation==
 
Excretion in breast milk unknown/contraindicated
 
==Contraindications==
 
Hypersensitivity to clofibrate or any component of the formulation; significant hepatic or renal dysfunction; primary biliary cirrhosis
 
==Warnings/Precautions==
 
Possible increased risk of malignancy and cholelithiasis. No evidence of cardiovascular mortality benefit. Anemia and leukopenia have been reported. Elevations in serum transaminases can be seen. Discontinue if lipid response is not seen. Use with caution in peptic ulcer disease. Flu-like symptoms may occur. Be careful in patient selection; this is not a first- or second-line choice. Other agents may be more suitable.
 
==Adverse Reactions==
 
===Frequency not defined===
 
Common: Gastrointestinal: Nausea, diarrhea
 
Less common:
 
Central nervous system: Headache, dizziness, fatigue
 
Gastrointestinal: Vomiting, loose stools, heartburn, flatulence, abdominal distress, epigastric pain
 
Neuromuscular & skeletal: Muscle cramping, aching, weakness, myalgia
 
===Frequency unknown===
 
Central nervous system: Fever
 
Cardiovascular: Chest pain, cardiac arrhythmia
 
Dermatologic: Rash, urticaria, pruritus, alopecia, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome; dry, brittle hair
 
Endocrine & metabolic: Polyphagia, gynecomastia, hyperkalemia
 
Gastrointestinal: Stomatitis, gallstones, pancreatitis, gastritis, peptic ulcer, weight gain
 
Genitourinary: Impotence, decreased libido
 
Hematologic: Leukopenia, anemia, eosinophilia, agranulocytosis, thrombocytopenic purpura
 
Hepatic: Hepatomegaly, jaundice, liver function tests increased
 
Local: Thrombophlebitis
 
Neuromuscular & skeletal: Myalgia, myopathy, myositis, arthralgia, rhabdomyolysis, increased creatinine phosphokinase (CPK), rheumatoid arthritis, tremor
 
Ocular: Photophobic
 
Renal: Dysuria, hematuria, proteinuria, renal toxicity (allergic), rhabdomyolysis-induced renal failure
 
Miscellaneous: Diaphoresis increased, flu-like syndrome, systemic lupus erythematosus
 
Overdosage/Toxicology
Symptoms of overdose include nausea, vomiting, diarrhea, and GI distress. Treatment is supportive.
 
==Drug Interactions==
Substrate of CYP3A4 (minor); Inhibits CYP2A6 (weak); Induces CYP2B6 (weak), 2E1 (weak), 3A4 (weak)
 
Chlorpropamide: May increase risk of hypoglycemia.
 
Furosemide: Blood levels of furosemide and fibric acid derivatives (ie, clofibrate and fenofibrate) may be increased during concurrent dosing (particularly in hypoalbuminemia). Limited documentation; monitor for increased effect/toxicity.
 
HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin) may increase the risk of myopathy and rhabdomyolysis. The manufacturer warns against the concomitant use. However, combination therapy with statins has been used in some patients with resistant hyperlipidemias (with great caution).
 
Insulin: Hypoglycemic effects may be potentiated by an unknown mechanism.
 
Probenecid may decrease the clearance of clofibrate.
 
Rifampin: Decreased clofibrate blood levels.
 
Sulfonylureas (including glyburide, glipizide): Hypoglycemic effects may be potentiated by an unknown mechanism.
 
Warfarin: Increased hypoprothrombinemic response; monitor INRs closely when clofibrate is initiated or discontinued.
 
==Mechanism of Action==
Mechanism is unclear but thought to reduce cholesterol synthesis and triglyceride hepatic-vascular transference
 
==Pharmacodynamics/Kinetics==
 
Absorption: Complete
 
Distribution: Vd: 5.5 L/kg; crosses placenta
 
Protein binding: 95%
 
Metabolism: Hepatic to an inactive glucuronide ester; intestinal transformation required to activate drug
 
Half-life elimination: 6-24 hours, significantly prolonged with renal impairment; Anuria: 110 hours
 
Time to peak, serum: 3-6 hours
 
Excretion: Urine (40% to 70%)
 
==Dosage==
Adults: Oral: 500 mg 4 times/day; some patients may respond to lower doses
 
Dosing interval in renal impairment:
 
Clcr >50 mL/minute: Administer every 6-12 hours
 
Clcr 10-50 mL/minute: Administer every 12-18 hours
 
Clcr<10 mL/minute: Avoid use
 
Hemodialysis: Elimination is not enhanced via hemodialysis; supplemental dose is not necessary
 
==Administration==
Administer with meals or milk if GI upset occurs.
 
==Monitoring Parameters==
Serum lipids, cholesterol and triglycerides, LFTs, CBC
 
==Test Interactions==
Increased creatine phosphokinase [CPK] (S); decreased alkaline phosphatase (S), cholesterol (S), glucose, uric acid (S)
 
==Patient Education==
Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed. May take with food or milk to reduce stomach upset.
 
This drug may have to be taken long-term; ongoing follow-up is essential. May cause nausea, vomiting, or stomach upset (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); headache, dizziness, fatigue (use care when driving or engaging in potentially hazardous tasks until response to drug is known); or muscle cramping or pain (if persistent, consult prescriber for analgesic).
 
Report chest pain, shortness of breath, irregular heartbeat, palpitations, severe stomach pain with persistent nausea and vomiting, persistent fever, sore throat, or unusual bleeding or bruising. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
 
==Nursing Implications==
Monitor serum lipids, LFTs, CBC
 
==Cardiovascular Considerations==
Fibric acids decrease triglycerides (TGs) by 20% to 50%, and increase HDL-cholesterol (HDL-C) by 10% to 35%. They decrease LDL-cholesterol (LDL-C) by 5% to 20%, however, LDL-C actually may increase by 10% to 30% when fibrates are initiated in patients with high TGs (>400 mg/dL).
 
==Dental Health: Effects on Dental Treatment==
 
Key adverse event(s) related to dental treatment: Stomatitis.
 
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
 
==Mental Health: Effects on Mental Status==
May cause sedation or dizziness
 
Mental Health: Effects on Psychiatric Treatment
Rare reports of agranulocytosis; use caution with clozapine and carbamazepine
 
==Dosage Forms==
Capsule: 500 mg


==References==
==References==
 
{{reflist|2}}
"Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)," JAMA , 2001, 285(19):2486-97.
 
Mahley RW and Bersot TP, "Drug Therapy for Hypercholesterolemia and Dyslipidemia," Goodman and Gilman's The Pharmacological Basis of Therapeutics , 10th ed, Hardman JE and Limbird LE, eds, New York, NY: McGraw-Hill, 2001, 993-5.
 
"WHO Cooperative Trial on Primary Prevention of Ischaemic Heart Disease With Clofibrate to Lower Serum Cholesterol: Final Mortality Follow-up. Report of the Committee of Principal Investigators," Lancet , 1984, 2(8403):600-4.
 
==International Brand Names==
Arterioflexin® (AT)
Atromid® (HK)
Atromidin® (LU)
Claripex (CA)
Clof® (CH)
Clofibrat Tripharma® (CH)
Elpi® (AR)
Levatrom® (IL)
Lipilim® (HK)
Novo-Fibrate (CA)


{{Lipid modifying agents}}
{{Lipid modifying agents}}


[[Category:Organochlorides]]
[[Category:Phenol ethers]]
[[Category:Fibrates]]
[[Category:Fibrates]]
[[Category:Prodrugs]]
[[Category:Cardiovascular Drugs]]
[[Category:Cardiology]]
[[Category:Drug]]
[[Category:Drugs]]
 
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Revision as of 21:53, 23 July 2014

Clofibrate
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • AU: B1
  • US: C (Risk not ruled out)
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • US: Discontinued
Pharmacokinetic data
Protein bindingVariable, 92–97% at therapeutic concentrations
MetabolismHydrolyzed to clofibric acid; hepatic glucuronidation
Elimination half-lifeHighly variable; average 18–22 hours. Prolonged in renal failure
ExcretionRenal, 95 to 99%
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC12H15ClO3
Molar mass242.698 g/mol
3D model (JSmol)
Boiling point148 °C (298.4 °F)
  (verify)

Clofibrate (tradename Atromid-S) is an organic compound. It is marketed as a fibrate. It is a lipid-lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood. It increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, and hence reduce the level of VLDL. It can increase the level of HDL as well.

Complications and controversies

It can induce SIADH, syndrome of inappropriate secretion of antidiuretic hormone ADH (vasopressin).

The World Health Organization Cooperative Trial on Primary Prevention of Ischaemic Heart Disease using clofibrate to lower serum cholesterol observed excess mortality in the clofibrate-treated group despite successful cholesterol lowering (47% more deaths during treatment with clofibrate and 5% after treatment with clofibrate) than the non-treated high cholesterol group. These deaths were due to a wide variety of causes other than heart disease, and remain "unexplained".[1]

Clofibrate was discontinued in 2002 due to adverse affects.

Synthesis

File:Clofibrate synthesis.svg
Clofibrate synthesis.[2]

References

  1. ↑ "WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the Committee of Principal Investigators". Lancet. 2 (8403): 600–4. September 1984. PMID 6147641.
  2. ↑ http://drugsynthesis.blogspot.co.uk/2012/04/laboratory-synthesis-of-clofibrate.html

Template:Lipid modifying agents

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