Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI51DLO0N)
Drug Name			Aminoglutethimide		Drug Info		Saquinavir		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antineoplastics				Anti-Hiv Agents
Structure

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

Drug Name		Aminoglutethimide				Saquinavir
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 Saquinavir caused by Aminoglutethimide mediated induction of CYP450 enzyme

Recommended Action
Management		Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, protease inhibitors should be used cautiously with agents that induce CYP450 3A4, particularly if only one PI is used in the antiretroviral regimen. Coadministration of atazanavir without ritonavir and carbamazepine, phenobarbital, or phenytoin is not recommended. Antiretroviral response should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the antiretroviral regimen adjusted as necessary.

References
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2	Barry M, Gibbons S, Back D, Mulcahy F "Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations." Clin Pharmacokinet 32 (1997): 194-209. [PMID: 9084959]
3	Brooks J, Daily J, Schwamm L "Protease inhibitors and anticonvulsants." AIDS Clin Care 9 (1997): 87,90. [PMID: 11364776]
4	Canadian Pharmacists Association.
5	Hugen PWH, Burger DM, Brinkman K, terHofstede HJM, Schuurman R, Koopmans PP, Hekster YA "Carbamazepine-indinavir interaction causes antiretroviral therapy failure." Ann Pharmacother 34 (2000): 465-70. [PMID: 10772431]
6	Liedtke MD, Lockhart SM, Rathbun RC "Anticonvulsant and antiretroviral interactions." Ann Pharmacother 38 (2004): 482-9. [PMID: 14970370]
7	Product Information. Agenerase (amprenavir). Glaxo Wellcome, Research Triangle Pk, NC.
8	Product Information. Aptivus (tipranavir). Boehringer-Ingelheim, Ridgefield, CT.
9	Product Information. Crixivan (indinavir). Merck & Co, Inc, West Point, PA.
10	Product Information. Fortovase (saquinavir) Roche Laboratories, Nutley, NJ.
11	Product Information. Invirase (saquinavir). Roche Laboratories, Nutley, NJ.
12	Product Information. Lexiva (fosamprenavir). GlaxoSmithKline, Research Triangle Park, NC.
13	Product Information. Prezista (darunavir). Ortho Biotech Inc, Bridgewater, NJ.
14	Product Information. Reyataz (atazanavir). Bristol-Myers Squibb, Princeton, NJ.
15	Product Information. Viracept (nelfinavir). Agouron Pharma Inc, La Jolla, CA.
16	Sommadossi JP "HIV protease inhibitors: pharmacologic and metabolic distinctions." AIDS 13 (1999): s29-40. [PMID: 10546783]
17	Durant J, Clevenbergh P, Garraffo R, Halfon P, Icard S, DelGiudice P, Montagne N, Schapiro JM, Dellamonica P "Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study." Aids 14 (2000): 1333-9. [PMID: 10930147]