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Menebar Ilmu Pengetahuan

Metabolisme Clopidogrel (Plavix)

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Clopidogrel adalah suatu prodrug yang secara klinis digunakan dengan aksi menghambat agregasi platelet. Obat ini mampu menurunkan risiko kejadian trombosis pada pasien dengan riwayat penyakit arterosklerosis, seperti stroke atau infark myokard. Dari sejumlah trial pada 19.185 pasien, menunjukkan clopidogrel superior dibandig aspirin dalam menurunkan kerjadian iskemik dari 5,83% manjadi 5,23%.

Clopidogrel memerlukan oksidasi oleh sitokrom p450 hepatik untuk menghasilkan metabolit aktif yang menghambat agragasi platelet terinduksi ADP. Bagaimanapun, hanya sedikit saja yang dimetabolisme olah p450, sebagian besar terhidrolisis oleh esterase menjadi derivat asam karboksilat tidak aktif sampai 85% bersirkulasi di plasma. Clopidogrel sendiri tidak terdeteksi di plasma. p450 mengkatalis oksidasi cincin tiopen pada clopidogrel menjadi 2-oksoclopidogrel, kemudian dioksidasi lebih lanjut sehingga terjadi pembukaan cincin tiopen membentuk gugus karboksil dan tiol. Gugus tiol membentuk ikatan disulfida dengan P2Y12 ADP-reseptor pada platelet. ADP tidak dapat berikatan kovalen dengan reseptor termodifikasi, dimana secara normal mengaktivasi glikoprotein kompleks GPIIb/IIIa yang berikatan dengan fibrinogen dan menginisiasi pembentukan clot.

Clopidogrel secara stuktur mirip dengan tienopiridin lain seperti tiklopidin, asam tienilat, dan CS-747. Senyawa-senyawa ini secara ekstensif sudah dikarakterisasi dan dimetabolisme oleh P450. Ticlopidin, dimetabolisme oleh CYP2C19, is also a suicide inhibitor of CYP2C19 and a known competitive inhibitor of CYP2D6 .

Tienilic acid is both oxidized by, and a suicide inhibitor of, human CYP2C9.

The third thienopyridine, CS-747, is oxidized by human CYP3A4 and 2B6. The human P450 responsible for oxidation of clopidogrel has not been identified, but it has been suggested that clopidogrel is oxidized by rat CYP1A2.

Atorvastatin, the most widely prescribed pharmaceutical for the prevention of hypercholesterolemia, is a member of the “statin” family. The statins are a group of HMG-CoA reductase inhibitors that inhibit cholesterol biosynthesis by binding to the active site of HMGCoA reductase (Igel et al., 2001). Atorvastatin is administered as the calcium salt of atorvastatin acid and is rapidly converted to its lactone form by a number of enzymatic processes, including acyl CoAsynthase (Prueksaritanont et al., 2001), paraoxonase (Teiber et al., 2002), and glucuronosyltransferases (Prueksaritanont et al., 2002).

Conversely, the lactone form of atorvastatin undergoes hydrolysis back to atorvastatin acid through the action of esterases. Clinical studies have demonstrated that the serum concentration of atorvastatin acid and lactone are similar in vivo (Kantola et al., 1998), indicating that the two forms of atorvastatin are in dynamic equilibrium in vivo. Both forms of atorvastatin are hydroxylated by CYP3A4, but the Km for atorvastatin lactone hydroxylation is 1.4 _M, _20 times lower than the Km of 25 _M for atorvastatin acid hydroxylation. The greater affinity of atorvastatin lactone for CYP3A4 indicates that the primary route of atorvastatin metabolism in humans is via the lactone (Jacobsen et al., 2000).

Clinical studies have demonstrated that atorvastatin inhibits the antiplatelet activity of clopidogrel (Lau et al., 2000). More recently, the anti-platelet activity of clopidogrel was observed to be inhibited in vivo by the CYP3A4 inhibitors erythromycin and troleandomycin and stimulated by the CYP3A4 inducer, rifampin (Lau et al., 2002). In this study, in vitro experiments have been performed in an attempt to unambiguously identify the human P450s responsible for clopidogrel oxidation.

Further information:

Diambil dari pendauluan journal DRUG METABOLISM AND DISPOSITION, Vol. 31, No. 01, 2003

slide ppt

http://www.plavix.com/Index.aspx

http://www.rxlist.com/plavix-drug.htm

http://www.drugs.com/plavix.html

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menebar ilmu pengetahuan

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