Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI4ZK3JR5)
Drug Name			Nevirapine		Drug Info		Methadone		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Anti-Hiv Agents				Analgesics
Structure

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

Drug Name		Nevirapine				Methadone
Mechanism		CYP450 3A4 inducer				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		Increased metabolism of Methadone caused by Nevirapine mediated induction of CYP450 enzyme

Recommended Action
Management		Caution is advised if efavirenz or nevirapine is prescribed to patients treated with methadone. Pharmacologic response to methadone should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of NNRTI therapy in patients who are stabilized on their methadone regimen. Following cessation of NNRTI therapy, it takes approximately 2 to 3 weeks for enzyme activity to return to pre-induction levels. Thus, if NNRTI therapy is discontinued due to adverse events or antiretroviral failure, methadone dosage should be gradually reduced over 2 to 3 weeks to pre-NNRTI levels. For patients treated with efavirenz, clinicians must also bear in mind that neurological adverse effects such as dizziness, headache, insomnia, vivid dreams, nightmares, and agitation may occur in up to 25% of patients shortly (within the first several days) after starting efavirenz. These symptoms may be self-limiting and should be clinically differentiated from symptoms of methadone withdrawal so as to avoid unnecessary increases in methadone dosage and the risk of toxicity.

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	Back D, Gibbons S, Khoo S "Pharmacokinetic drug interactions with nevirapine." J Acquir Immune Defic Syndr 34 Suppl 1 (2003): S8-14. [PMID: 14562853]
3	Clarke SM, Mulcahy FM, Reynolds HE, Gibbons SE, Barry MG, Back DJ "The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz." Br J Clin Pharmacol 51 (2001): 213-7. [PMID: 11298066]
4	Clarke SM, Mulcahy FM, Tjia J, et al. "Pharmacokinetic Interactions of Nevirapine and Methadone and Guidelines for Use of Nevirapine to Treat Injection Drug Users." Clin Infect Dis 33 (2001):. [PMID: 11568856]
5	Heelon MW, Meade LB "Methadone withdrawal when starting an antiretroviral regimen including nevirapine." Pharmacotherapy 19 (1999): 471-2. [PMID: 10212021]
6	Marzolini C, Troillet N, Telenti A, Baumann P, Decosterd LA, Eap CB "Efavirenz decreases methadone blood concentrations." Aids 14 (2000): 1291-2. [PMID: 10894303]
7	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]
8	Pinzani V, Faucherre V, Peyriere H, Blayac JP "Methadone withdrawal symptoms with nevirapine and efavirenz." Ann Pharmacother 34 (2000): 405-7. [PMID: 10917395]