Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI4JN2607)
Drug Name			Lovastatin		Drug Info		Nefazodone		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Statins/Antihyperlipidemic Agents				Antidepressants
Structure

Mechanism of Lovastatin-Nefazodone Interaction (Severity Level: Major)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Lovastatin				Nefazodone
Mechanism		CYP450 3A4 substrate				CYP450 3A4 inhibitor
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		Decreased metabolism of Lovastatin caused by Nefazodone mediated inhibition of CYP450 enzyme

Recommended Action
Management		Due to the potential for severe interaction, concomitant use of simvastatin or lovastatin with potent CYP450 3A4 inhibitors such as nefazodone is considered contraindicated. Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are probably safer alternatives, since they are not metabolized by CYP450 3A4, although pravastatin was cited in a case report of suspected interaction that resulted in asymptomatic increases in creatine kinase levels. 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	Alderman CP "Possible interaction between nefazodone and pravastatin." Ann Pharmacother 33 (1999): 871. [PMID: 10466919]
2	Alderman CP "Possible interaction between nefazodone and pravastatin." Ann Pharmacother 34 (2000): 538-9. [PMID: 10466919]
3	Bottorf MB "Possible interaction between nefazodone and pravastatin." Ann Pharmacother 34 (2000): 538. [PMID: 10772447]
4	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
5	Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F "New insights into the pharmacodynamic and pharmacokinetic properties of statins." Pharmacol Ther 84 (1999): 413-28. [PMID: 10665838]
6	Jacobson RH, Wang P, Glueck CJ "Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone." JAMA 277 (1997): 296. [PMID: 9002485]
7	Jody DN "Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone." JAMA 277 (1997): 296-7. [PMID: 9002485]
8	Karnik NS, Maldonado JR "Antidepressant and statin interactions: a review and case report of simvastatin and nefazodone-induced rhabdomyolysis and transaminitis." Psychosomatics 46 (2005): 565-8. [PMID: 16288136]
9	Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74. [PMID: 18563955]
10	Paoletti R, Corsini A, Bellosta S "Pharmacological interactions of statins." Atheroscler Suppl 3 (2002): 35-40. [PMID: 12044584]
11	Product Information. Advicor (lovastatin-niacin). Kos Pharmaceuticals, Miami, FL.
12	Product Information. Mevacor (lovastatin). Merck & Co, Inc, West Point, PA.
13	Product Information. Serzone (nefazodone). Bristol-Myers Squibb, Princeton, NJ.
14	Product Information. Zocor (simvastatin). Merck & Co, Inc, West Point, PA.
15	Skrabal MZ, Stading JA, Monaghan MS "Rhabdomyolysis associated with simvastatin-nefazodone therapy." South Med J 96 (2003): 1034-5. [PMID: 14570351]
16	Thompson M, Samuels S "Rhabdomyolysis with simvastatin and nefazodone." Am J Psychiatry 159 (2002): 1607. [PMID: 12202291]