Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIQZF6WVD)
Drug Name			Aminoglutethimide		Drug Info		Irinotecan		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antineoplastics				Antineoplastics
Structure

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

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

Recommended Action
Management		The antitumour activity of irinotecan may be reduced in patients treated with CYP450 3A4 inducers. Pharmacologic response to irinotecan should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the irinotecan dosage adjusted as necessary.

References
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2	Di YM, Li CG, Xue CC, Zhou SF "Clinical drugs that interact with St. John's wort and implication in drug development." Curr Pharm Des 14 (2008): 1723-42. [PMID: 18673195]
3	Friedman HS, Petros WP, Friedman AH, et al "Irinotecan therapy in adults with recurrent or progressive malignant glioma." J Clin Oncol 17 (1999): 1516-25. [PMID: 10334539]
4	Innocenti F, Undevia SD, Ramirez J, et al. "A phase I trial of pharmacologic modulation of irinotecan with cyclosporine and phenobarbital." Clin Pharmacol Ther 76 (2004): 490-502. [PMID: 15536463]
5	Kuhn JG "Influence of anticonvulsants on the metabolism and elimination of irinotecan. A North American Brain Tumor Consortium preliminary report." Oncology (Williston Park 16(8 Suppl 7) (2002): 33-40. [PMID: 12199631]
6	Hu ZP, Yang XX, Chen X, et al. A mechanistic study on altered pharmacokinetics of irinotecan by St. John's wort.?Curr Drug Metab. 2007;8(2):157-171. [PMID: 17305494]
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8	Minami H, Lad TE, Nicholas MK, Vokes EE, Ratain MJ "Pharmacokinetics and pharmacodynamics of 9-aminocamptothecin infused over 72 hours in phase II studies." Clin Cancer Res 5 (1999): 1325-30. [PMID: 10389915]
9	Murry DJ, Cherrick I, Salama V, et al. "Influence of phenytoin on the disposition of irinotecan: a case report." J Pediatr Hematol Oncol 24 (2002): 130-3. [PMID: 11990699]
10	Product Information. Camptosar (irinotecan). Pharmacia and Upjohn, Kalamazoo, MI.
11	Product Information. Onivyde (irinotecan liposomal). Merrimack Pharmaceuticals, Cambridge, MA.
12	Hofland KF, Hansen S, Sorensen M, et al. Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme: A randomized phase II study.?Acta Oncol. 2014;53(7):939-944. [PMID: 24456504]
13	Santos A, Zanetta S, Cresteil T, et al "Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans." Clin Cancer Res 6 (2000): 2012-20. [PMID: 10815927]
14	Yonemori K, Takeda Y, Toyota E, Kobayashi N, Kudo K "Potential interactions between irinotecan and rifampin in a patient with small-cell lung cancer." Int J Clin Oncol 9 (2004): 206-9. [PMID: 15221608]
15	Zamboni WC, Gajjar AJ, Heideman RL, et al "Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma." Clin Cancer Res 4 (1998): 783-9. [PMID: 9533548]