Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIS1Y3NZT)
Drug Name			Fentanyl		Drug Info		Metreleptin		Drug Info
Drug Type		Small molecule				Hormones
Therapeutic Class		Narcotic Analgesics				Metabolic Agents

Mechanism of Fentanyl-Metreleptin Interaction (Severity Level: Moderate)
CYP450 enzyme induction Click to Show/Hide Mechanism Graph

Drug Name		Fentanyl				Metreleptin
Mechanism		CYP450 3A4 substrate				CYP450 3A4 inducer
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 metabolism of Fentanyl caused by Metreleptin mediated induction of CYP450 enzyme

Recommended Action
Management		Pharmacologic response to the opioid should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the opioid dosage adjusted as necessary.

References
1	Altice FL, Friedland GH, Cooney EL "Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone." AIDS 13 (1999): 957-62. [PMID: 10371177]
2	Bell J, Seres V, Bowron P, Lewis J, Batey R "The use of serum methadone levels in patients receiving methadone maintenance." Clin Pharmacol Ther 43 (1988): 623-9. [PMID: 3378383]
3	Bending MR, Skacel PO "Rifampicin and methadone withdrawal." Lancet 1 (1977): 1211. [PMID: 68314]
4	Cerner Multum, Inc. "Australian Product Information.".
5	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
6	Finelli PF "Phenytoin and methadone tolerance." N Engl J Med 294 (1976): 227. [PMID: 1244546]
7	Holmes VF "Rifampin-induced methadone withdrawal in AIDS." J Clin Psychopharmacol 10 (1991): 443-4. [PMID: 2286719]
8	Kreek MJ, Garfield JW, Gutjahr CL, Giusti LM "Rifampin-induced methadone withdrawal." N Engl J Med 294 (1976): 1104-6. [PMID: 1256526]
9	Liu S-J, Wang RI "Case report of barbiturate-induced enhancement of methadone metabolism and withdrawal syndrome." Am J Psychiatry 141 (1984): 1287-8. [PMID: 6486271]
10	Otero MJ, Fuertes A, Sanchez R, Luna G "Nevirapine-induced withdrawal symptoms in HIV patients on methadone maintenance programme: an alert." AIDS 13 (1999): 1004-5. [PMID: 10371190]
11	Pinzani V, Faucherre V, Peyriere H, Blayac JP "Methadone withdrawal symptoms with nevirapine and efavirenz." Ann Pharmacother 34 (2000): 405-7. [PMID: 10917395]
12	Product Information. Butorphanol Tartrate (butorphanol). Apotex Corporation, Weston, FL.
13	Product Information. Diskets (methadone). Cebert Pharmaceuticals Inc, Birmingham, AL.
14	Product Information. Duragesic Transdermal System (fentanyl). Janssen Pharmaceutica, Titusville, NJ.
15	Product Information. Ionsys (fentanyl). Ortho McNeil Pharmaceutical, Raritan, NJ.
16	Product Information. OxyContin (oxycodone). Purdue Frederick Company, Norwalk, CT.
17	Product Information. Zohydro ER (HYDROcodone). Zogenix, Inc, San Diego, CA.
18	Raistrick D, Hay A, Wolff K "Methadone maintenance and tuberculosis treatment." BMJ 313 (1996): 925-6. [PMID: 8876100]
19	Tong TG, Pond SM, Kreek MJ, et al "Phenytoin-induced methadone withdrawal." Ann Intern Med 94 (1981): 349-51. [PMID: 7224382]