Clopidogrel 587970 225166191 2008-07-12T06:34:34Z 202.69.42.210 /* Pharmacokinetics and Metabolism */ {{drugbox | |image= Clopidogrel chemical structure.png |width=250 |image2=Clopidogrel 3D.png |width2=200 |IUPAC_name = (+)-(''S'')-methyl 2-(2-chlorophenyl)-<br />2-(6,7-dihydrothieno[3,2-''c'']pyridin-5(4''H'')-yl)acetate |CAS_number = 113665-84-2 | ATC_prefix=B01 | ATC_suffix=AC04 | PubChem=60606 | DrugBank=APRD00444 | C=16 | H=16 | Cl=1 | N=1 | O=2 | S=1 |molecular_weight = 321.82 g/mol | smiles = COC(=O)C(N1CCc2sccc2C1)c1ccccc1Cl |bioavailability = >50% |protein_bound= 94–98% |metabolism = [[Liver|Hepatic]] |elimination_half-life = 7–8 hours (inactive metabolite) |excretion = 50% [[renal]]<br />46% [[biliary]] |pregnancy_AU = B1 |pregnancy_US = B |pregnancy_category = |legal_AU = S4 |legal_UK = POM |legal_US = Rx-only |legal_status = |routes_of_administration = Oral }} [[Image:Plavix 2007-04-19.jpg|thumb|right|272px|A box of Plavix]] '''Clopidogrel''' is a potent oral [[Antiplatelet drug|antiplatelet agent]] often used in the treatment of [[coronary artery disease]], [[peripheral vascular disease]], and [[cerebrovascular disease]]. It is marketed by [[Bristol-Myers Squibb]] and [[Sanofi-Aventis]] under the [[trade name]]s '''Plavix''' and '''Iscover''', and by [[Sun Pharmaceuticals]] under the [[trade name]] '''Clopilet'''. It works by blocking a receptor called [[P2Y12]]. Adverse effects include [[hemorrhage]]. == Pharmacology == The mechanism of action of clopidogrel is an irreversible blockade of the [[adenosine diphosphate]] (ADP) receptor on [[platelet]] cell membranes. This receptor is named [[P2Y12]] and is important in platelet aggregation, the cross-linking of platelets by [[fibrin]]. The blockade of this receptor inhibits platelet aggregation by blocking activation of the [[glycoprotein IIb/IIIa]] pathway. Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loading-dose of 300-600 mg is usually administered. == Clinical use == === Indications === Clopidogrel is indicated for:<ref name="Rossi">Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> * Prevention of vascular [[ischemia|ischaemic]] events in patients with symptomatic [[atherosclerosis]] * Acute coronary syndrome without ST-segment elevation ([[myocardial infarction|NSTEMI]]), along with aspirin * ST elevation MI (STEMI) It is also used, along with aspirin, for the prevention of thromboembolism after placement of intracoronary stent. <ref name="Rossi"> </ref> International guidelines granted the highest grade of recommendation for NSTE-ACS, PCI and stent, for Clopidogrel in addition to Aspirin. Consensus-based therapeutic guidelines recommend also the use of clopidogrel, instead of [[aspirin]], in patients requiring antiplatelet therapy but with a history of gastric ulceration, as inhibition of the synthesis of prostaglandins by aspirin (acetylsalicylic acid) can exacerbate this condition. A recent study has shown that in patients with healed aspirin-induced ulcers, however, patients receiving aspirin plus the [[proton pump inhibitor]] [[esomeprazole]] had a lower incidence of recurrent ulcer bleeding than patients receiving clopidogrel. <ref name="pmid15659723">{{cite journal |author=Chan FK, Ching JY, Hung LC, ''et al'' |title=Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding |journal=N. Engl. J. Med. |volume=352 |issue=3 |pages=238–44 |year=2005 |pmid=15659723 |doi=10.1056/NEJMoa042087}}</ref> === Dosage forms === Clopidogrel is marketed as '''clopidogrel bisulfate''' ('''clopidogrel hydrogen sulfate'''), most commonly under the trade names '''Plavix''', as 75 mg oral tablets. == Pharmacokinetics and Metabolism ==it is rapidly absorbed ofter oral administation of repeated doses of 75mg clopidogrel. [[Image:Clopidogrel active metabolite.png|250px|thumb|The active metabolite of clopidogrel <ref name="metabolite">{{cite journal | author = J. M. Pereillo, M. Maftouh, A. Andrieu, M. F. Uzabiaga, O. Fedeli, P. Savi, M. Pascal, J. M. Herbert, J. P. Maffrand, C. Picard | year = 2002 | title = Structure and stereochemistry of the active metabolite of clopidogrel | journal = Drug Metab. Dispos. | volume = 30 | issue = 11 | pages = 1288–1295 | pmid = 12386137 | doi = | url = http://dmd.aspetjournals.org/cgi/reprint/30/11/1288.pdf }}</ref>]] After repeated 75-mg oral doses of clopidogrel (base), plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.000258 mg/L) beyond 2 hours after dosing. Clopidogrel is a pro-drug which requires metabolism by the liver for its activation.The active metabolite has an elimination half-life of about 8 hours and acts by forming a disulfide bridge with the platelet ADP receptor. Following an oral dose of <sup>14</sup>C-labeled clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing. ''Effect of Food:'' Administration of PLAVIX (clopidogrel bisulfate) with meals did not significantly modify the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite. ''Absorption and Distribution:'' Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg clopidogrel (base), with peak plasma levels (appx. 3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to does) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites. Clopidogrel and the main circulating metabolite bind reversibly ''in vitro'' to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable ''in vitro'' up to a concentration of 110 μg/mL. ''Metabolism and Elimination: In vitro'' and ''in vivo'', clopidogrel undergoes rapid hydrolysis into its [[carboxylic acid]] derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed. == Adverse effects == Serious [[adverse drug reaction]]s associated with clopidogrel therapy include: * Severe [[neutropenia]] (Incidence: 5/10,000) * [[Thrombotic thrombocytopenic purpura]] (TTP) (Incidence: 4/1,000,000 patients treated) * [[Hemorrhage]] - The incidence of hemorrhage may be increased by the co-administration of [[aspirin]]. ** Gastrointestinal Hemorrhage (Incidence: 2.0%) ** Cerebral Hemorrhage (Incidence: 0.1 to 0.4%) * Erectile Dysfunction (Incidence as yet unknown) == Marketing == Plavix has been the 2nd top selling drug in the world over the past years [http://imshealth.com/vgn/images/portal/CIT_40000873/56/42/83743762Top%2010%20Global%20Products%202007.pdf] and was still growing by over 20% in 2007. Plavix is marketed worldwide in nearly 110 countries. In 2006, generic clopidogrel was briefly marketed by [[Apotex]], a [[Canada|Canadian]] generic [[pharmaceutical company]] before a court order halted further production until resolution of a patent infringement case brought by [[Bristol-Myers Squibb]].<ref>{{cite web |url=http://www.earthtimes.org/articles/show/news_press_release,32577.shtml |title=Preliminary Injunction Against Apotex Upheld on Appeal - Press Release |accessdate=2007-09-05 |format= |work=}}</ref> The court ruled that Bristol-Myers Squibb's patent was valid and has patent protection until November 2011.<ref>{{cite web |url=http://www.reuters.com/article/businessNews/idUSN1931607820070619?pageNumber=1 |title=U.S. judge upholds Bristol, Sanofi patent on Plavix | Reuters |accessdate=2007-09-05 |format= |work=}}</ref> In 2007, the production was halted to many retail pharmacies and will be changing back to Plavix. In 2005 it was reported that Plavix was the world's second highest selling pharmaceutical with sales of US$5.9 billion.<ref>{{cite web |url=http://www.imshealth.com/ims/portal/front/articleC/0,2777,6599_77478579_77479663,00.html |title=IMS HEALTH |accessdate=2007-09-05 |format= |work=}}</ref> Generic clopidogrel is also produced by several pharmaceutical companies in India at significantly lower retail prices, up to 1/30th of the price. == Research into migraine treatment == Dr. John Chambers, a cardiologist in London, recently reported that the use of clopidogrel in patients with a history of migraines worked "spectacularly well" in some cases. A wider study is planned and has received considerable support from within the British medical community. <ref>{{cite news | first = Laurance | last = Jeremy | title = Drug promises end to migraine misery | url = http://news.independent.co.uk/health/article3284878.ece | work = Independent Online Edition | publisher = Independent News and Media Limited | date = 2007-12-26 | accessdate = 2007-12-26 }}</ref> == References == <references/> == External links == * {{DailyMed|3418}} * [http://www.plavix.com Plavix : Information for the General Public] * [http://www.ptca.org/forumtopics/topic20050423.html Plavix, Aspirin and Stents : Patients' Forum : Angioplasty.Org] * [http://news.independent.co.uk/health/article3284878.ece Drug promises end to migraine misery] {{Antithrombotics}} [[Category:Antiplatelet drugs]] [[Category:ADP receptor inhibitors]] [[Category:Sanofi-Aventis]] [[Category:Thiophenes]] [[de:Clopidogrel]] [[fr:Clopidogrel]] [[it:Clopidogrel]] [[hu:Klopidrogél]] [[nl:Clopidogrel]] [[pl:Klopidogrel]] [[pt:Clopidogrel]] [[ru:Клопидогрель]]