Details of Drug Interaction | MecDDI

Drug General Information (ID: DDITKM198H)
Drug Name			Fluconazole		Drug Info		Lovastatin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antifungal Agents				Statins/Antihyperlipidemic Agents
Structure

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

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

Recommended Action
Management		The benefits of using azole antifungal agents with statins that are substrates of CYP450 3A4 should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. If coadministration is required, a lower initial and maintenance dosage of the statin should be considered. Close monitoring for musculoskeletal toxicity is recommended, particularly during the initial months of therapy and following a dosage increase of either drug. Pitavastatin, pravastatin, and rosuvastatin may be safer alternatives, since they are not metabolized by CYP450 3A4. Fluvastatin may also be used with azole antifungal agents except fluconazole and voriconazole, both of which can inhibit fluvastatin metabolism via CYP450 2C9. alternatively, an interruption of the statin may be considered during treatment with an azole antifungal agent. 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	Akram K, Rao S, Parker M "A lesson for everyone in drug-drug interactions." Int J Cardiol 118 (2007): e19-20. [PMID: 17368833]
2	Gilad R, Lampl Y "Rhabdomyolysis induced by simvastatin and ketoconazole treatment." Clin Neuropharmacol 22 (1999): 295-7. [PMID: 10516882]
3	Horn M "Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals." Arch Dermatol 132 (1996): 1254. [PMID: 8859048]
4	Itakura H, Vaughn D, Haller DG, O'Dwyer PJ "Rhabdomyolysis from cytochrome p-450 interaction of ketoconazole and simvastatin in prostate cancer." J Urol 169 (2003): 613. [PMID: 12544321]
5	Kantola T, Kivisto KT, Neuvonen PJ "Effect of itraconazole on cerivastatin pharmacokinetics." Eur J Clin Pharmacol 54 (1999): 851-5. [PMID: 10027660]
6	Kantola T, Kivisto KT, Neuvonen PJ "Effect of itraconazole on the pharmacokinetics of atorvastatin." Clin Pharmacol Ther 64 (1998): 58-65. [PMID: 9695720]
7	Kivisto KT, Kantola T, Neuvonen PJ "Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin." Br J Clin Pharmacol 46 (1998): 49-53. [PMID: 9690949]
8	Lees RS, Lees AM "Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole." N Engl J Med 333 (1995): 664-5. [PMID: 7637734]
9	Lomaestro BM, Piatek MA "Update on drug interactions with azole antifungal agents." Ann Pharmacother 32 (1998): 915-28. [PMID: 9762380]
10	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]
11	Neuvonen PJ, Jalava KM "Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid." Clin Pharmacol Ther 60 (1996): 54-61. [PMID: 8689812]
12	Neuvonen PJ, Kantola T, Kivisto KT "Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole." Clin Pharmacol Ther 63 (1998): 332-41. [PMID: 9542477]
13	Stein CA, Goel S, Ghavamian R "Hepatitis and rhabdomyolysis in a patient with hormone refractory prostate cancer on ketoconazole and concurrent lovastatin therapy." Invest New Drugs 25 (2007): 277-8. [PMID: 17216557]
14	Watkins JL, Atkinson BJ, Pagliaro LC "Rhabdomyolysis in a prostate cancer patient taking ketoconazole and simvastatin: case report and review of the literature." Ann Pharmacother 45 (2011): e9. [PMID: 21304039]