Details of Drug-Drug Interaction
| Drug General Information (ID: DDINODC3JM) | |||||||||
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| Drug Name | Zileuton | Drug Info | Lomitapide | Drug Info | |||||
| Drug Type | Small molecule | Small molecule | |||||||
| Therapeutic Class | Antiinflammatory Agents | Antihyperammonia Agents | |||||||
| Structure | |||||||||
| Mechanism of Zileuton-Lomitapide Interaction (Severity Level: Major) | |||||||||
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| CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph | |||||||||
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| Drug Name | Zileuton | Lomitapide | |||||||
| Mechanism 1 | CYP450 3A4 inhibitor | CYP450 3A4 substrate | |||||||
| Key Mechanism Factor 1 | |||||||||
| Factor Name | Cytochrome P450 3A4 |
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Structure
Sequence
MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFDMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIAEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSMDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVFPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSIIFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVNETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFSKKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGGLLQPEKPVVLKVESRDGTVSGA
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| 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
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| Mechanism Description |
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| Increased risk of hepatotoxicity Click to Show/Hide Mechanism Graph | |||||||||
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| Drug Name | Zileuton | Lomitapide | |||||||
| Mechanism 2 | Hepatotoxicity | Hepatotoxicity | |||||||
| Key Mechanism Factor 2 | |||||||||
| Factor Name | Hepatotoxicity | ||||||||
| Factor Description | Combination of drugs that can induce hepatotoxicity may increase the risk of liver injury. Symptoms vary depending on the level of exposure and the total extent of liver damage, and may cause few symptoms if the damage is mild, and eventually lead to liver failure in patients with severe damage. | ||||||||
| Mechanism Description |
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| Recommended Action | |||||||||
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| Management | The maximum recommended dosage of lomitapide is 30 mg daily when used in combination with weak CYP450 3A4 inhibitors such as amiodarone, atorvastatin, bicalutamide, cyclosporine, danazol, isoniazid, ivacaftor, lapatinib, nilotinib, pazopanib, zafirlukast, and zileuton. Caution is advised because these agents may also have additive hepatotoxic effects with lomitapide. Patients treated with lomitapide should have serum ALT, AST, alkaline phosphatase, and total bilirubin monitored prior to initiation of treatment and regularly during treatment in accordance with the product labeling, and the dosing adjusted or interrupted as necessary. Since alcohol may increase levels of hepatic fat and induce or exacerbate liver injury, the manufacturer recommends that patients taking lomitapide not consume more than one alcoholic drink per day. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. | ||||||||
| References | |||||||||||||||||||
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| 1 | Product Information. Juxtapid (lomitapide). Aegerion Pharmaceuticals Inc, Cambridge, MA. | ||||||||||||||||||