Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIVECW1UI)
Drug Name			Clopidogrel		Drug Info		Atorvastatin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiplatelet Agents				Statins/Antihyperlipidemic Agents
Structure

Mechanism of Clopidogrel-Atorvastatin Interaction (Severity Level: Moderate)
Competitive inhibition of metabolic enzyme Click to Show/Hide Mechanism Graph

Drug Name		Clopidogrel				Atorvastatin
Mechanism		CYP450 3A4 substrate				CYP450 3A4 substrate
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 3A4				× Structure Sequence MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFDMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIAEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSMDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVFPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSIIFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVNETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFSKKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGGLLQPEKPVVLKVESRDGTVSGA
		Gene Name		CYP3A4
		Uniprot ID		CP3A4_HUMAN
		KEGG Pathway		hsa:1576
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:20702771, PubMed:19965576, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:2732228, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:21576599, PubMed:21490593). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:14559847, PubMed:12865317). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:2732228, PubMed:15373842, PubMed:15764715, PubMed:22773874). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:2732228, PubMed:15373842, PubMed:15764715). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981). Click to Show/Hide
Mechanism Description		Increased plasma concentrations of Clopidogrel and Atorvastatin due to competitive inhibition of the same metabolic pathway

Recommended Action
Management		Until more information is available, monitoring for altered efficacy of clopidogrel may be advisable if atorvastatin is coadministered with clopidogrel. Pravastatin, fluvastatin, and rosuvastatin are not metabolized by CYP450 3A4 and are theoretically not expected to interact with clopidogrel.

References
1	Clarke TA, Waskell LA "The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin." Drug Metab Dispos 31 (2003): 53-9. [PMID: 12485953]
2	Damkier P "Atorvastatin and clopidogrel." Circulation 108 (2003): e96 author reply e96. [PMID: 14517157]
3	Lau WC, Waskell LA, Watkins PB, et al. "Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction." Circulation 107 (2003): 32-7. [PMID: 12515739]
4	Neubauer H, Gunesdogan B, Hanefeld C, Spiecker M, Mugge A "Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function - a flow cytometry study." Eur Heart J 24 (2003): 1744-1749. [PMID: 14522569]
5	Saw J, Steinhubl SR, Berger PB, et al. "Lack of Adverse Clopidogrel-Atorvastatin Clinical Interaction From Secondary Analysis of a Randomized, Placebo-Controlled Clopidogrel Trial." Circulation 108 (2003): 921-924. [PMID: 12925453]
6	Serebruany VL, Steinhubl SR, Hennekens CH "Are antiplatelet effects of clopidogrel inhibited by atorvastatin? A research question formulated but not yet adequately tested." Circulation 107 (2003): 1568-9. [PMID: 12668486]
7	Shechter M "Atorvastatin and the ability of clopidogrel to inhibit platelet aggregation." Circulation 107 (2003): e210 author reply e210. [PMID: 12796420]