Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI2J1YRT7)
Drug Name			Triamcinolone		Drug Info		Tucatinib		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiinflammatory Agents				Antineoplastics/Her2 Inhibitors
Structure

Mechanism of Triamcinolone-Tucatinib Interaction (Severity Level: Major)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Triamcinolone				Tucatinib
Mechanism		CYP450 3A4 substrate				CYP450 3A4 inhibitor
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		Decreased metabolism of Triamcinolone caused by Tucatinib mediated inhibition of CYP450 enzyme

Recommended Action
Management		The possibility of increased corticosteroid effects should be considered when triamcinolone is used with potent CYP450 3A4 inhibitors. Some authorities advise against concomitant use unless the potential benefit outweighs the risk. If coadministration is necessary, a lower dosage of triamcinolone may be appropriate. Patients should be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and menstrual disorders. Other systemic glucocorticoid effects may include adrenal suppression, immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents. Following extensive use with a potent CYP450 3A4 inhibitor, a progressive dosage reduction may be required over a longer period if triamcinolone is to be withdrawn from therapy, as there may be a significant risk of adrenal suppression.

References
1	Agencia Espaola de Medicamentos y Productos Sanitarios Healthcare "Centro de informacion online de medicamentos de la AEMPS - CIMA.".
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3	Dort K, Padia S, Wispelwey B, Moore CC "Adrenal suppression due to an interaction between ritonavir and injected triamcinolone: a case report." AIDS Res Ther 6 (2009): 10. [PMID: 19505306]
4	EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports.".
5	Fessler D, Beach J, Keel J, Stead W "Iatrogenic hypercortisolism complicating triamcinolone acetonide injections in patients with HIV on ritonavir-boosted protease inhibitors." Pain Physician 15 (2012): 489-93. [PMID: 23159966]
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7	Hall JJ, Hughes CA, Foisy MM, Houston S, Shafran S "Iatrogenic Cushing syndrome after intra-articular triamcinolone in a patient receiving ritonavir boosted darunavir." Int J STD AIDS (2013):. [PMID: 23970582]
8	Levine D, Ananthakrishnan S, Garg A "Iatrogenic Cushing syndrome after a single intramuscular corticosteroid injection and concomitant protease inhibitor therapy." J Am Acad Dermatol 65 (2011): 877-8. [PMID: 21920248]
9	McConkey HZ, Williams H, Kulasegaram R, Graham E "Orbital floor triamcinolone causing Cushing's syndrome in a patient treated with Kaletra for HIV 1." BMJ Case Rep 2013 (2013):. [PMID: 23440982]
10	Sadarangani S, Berg ML, Mauck W, Rizza S "Iatrogenic Cushing Syndrome Secondary to Ritonavir-Epidural Triamcinolone Interaction: An Illustrative Case and Review." Interdiscip Perspect Infect Dis 2014 (2014): 849432. [PMID: 24895495]
11	Schwarze-Zander C, Klingmuller D, Klumper J, Strassburg CP, Rockstroh JK "Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature." Infection (2013):. [PMID: 23873267]
12	Grierson MJ, Harrast MA "Iatrogenic Cushing Syndrome After Epidural Steroid Injections for Lumbar Radiculopathy in an HIV-Infected Patient Treated With Ritonavir: A Case Report Highlighting Drug Interactions for Spine Interventionalists." PM R 4 (2012): 234-7. [PMID: 22443962]