Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI4FG3RSK)
Drug Name			Rosuvastatin		Drug Info		Grazoprevir		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Statins/Antihyperlipidemic Agents				Antiviral Agents
Structure

Mechanism of Rosuvastatin-Grazoprevir Interaction (Severity Level: Major)
Transporter inhibition Click to Show/Hide Mechanism Graph

Drug Name		Rosuvastatin				Grazoprevir
Mechanism		BCRP substrate				BCRP inhibitor
Key Mechanism Factor 1
		Factor Name		ATP-binding cassette transporter G2				× Structure Sequence MSSSNVEVFIPVSQGNTNGFPATASNDLKAFTEGAVLSFHNICYRVKLKSGFLPCRKPVEKEILSNINGIMKPGLNAILGPTGGGKSSLLDVLAARKDPSGLSGDVLINGAPRPANFKCNSGYVVQDDVVMGTLTVRENLQFSAALRLATTMTNHEKNERINRVIQELGLDKVADSKVGTQFIRGVSGGERKRTSIGMELITDPSILFLDEPTTGLDSSTANAVLLLLKRMSKQGRTIIFSIHQPRYSIFKLFDSLTLLASGRLMFHGPAQEALGYFESAGYHCEAYNNPADFFLDIINGDSTAVALNREEDFKATEIIEPSKQDKPLIEKLAEIYVNSSFYKETKAELHQLSGGEKKKKITVFKEISYTTSFCHQLRWVSKRSFKNLLGNPQASIAQIIVTVVLGLVIGAIYFGLKNDSTGIQNRAGVLFFLTTNQCFSSVSAVELFVVEKKLFIHEYISGYYRVSSYFLGKLLSDLLPMRMLPSIIFTCIVYFMLGLKPKADAFFVMMFTLMMVAYSASSMALAIAAGQSVVSVATLLMTICFVFMMIFSGLLVNLTTIASWLSWLQYFSIPRYGFTALQHNEFLGQNFCPGLNATGNNPCNYATCTGEEYLVKQGIDLSPWGLWKNHVALACMIVIFLTIAYLKLLFLKKYS
		Gene Name		BCRP
		Uniprot ID		ABCG2_HUMAN
		KEGG Pathway		hsa:9429
		Protein Family		ABC transporter superfamily
		Protein Function		Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity). Click to Show/Hide
Mechanism Description		Decreased clearance of Rosuvastatin due to the transporter inhibition by Grazoprevir

Recommended Action
Management		Caution is advised when statins such as atorvastatin, rosuvastatin, fluvastatin, lovastatin, and simvastatin are prescribed with elbasvir-grazoprevir. Atorvastatin dosage should not exceed 20 mg/day and rosuvastatin dosage should not exceed 10 mg/day according to the product labeling for elbasvir-grazoprevir. The lowest effective dose of fluvastatin, lovastatin, or simvastatin should be used some authorities recommend a maximum daily dose of 20 mg of these statins. In contrast, pitavastatin and pravastatin do not have clinically relevant interactions with elbasvir-grazoprevir, and no dosage adjustments are necessary. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

References
1	Cerner Multum, Inc. "Australian Product Information.".
2	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
3	Product Information. Zepatier (elbasvir-grazoprevir). Merck &amp Company Inc, Whitehouse Station, NJ.