Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIVL1OYE6)
Drug Name			Tretinoin		Drug Info		Conivaptan		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Keratolytic Agents				Vasopressin Antagonists
Structure

Mechanism of Tretinoin-Conivaptan Interaction (Severity Level: Moderate)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Tretinoin				Conivaptan
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 Tretinoin caused by Conivaptan mediated inhibition of CYP450 enzyme

Recommended Action
Management		Caution is advised when tretinoin is prescribed in combination with potent inhibitors of CYP450 2C8, 2C9, and/or 3A4. Patients should be closely monitored and advised to seek medical attention immediately if they develop early symptoms of pseudotumour cerebri such as headache, nausea, vomiting, visual disturbances, photosensitivity, and tinnitus.

References
1	Adamson PC "Pharmacokinetics of all-trans-retinoic acid: clinical implications in acute promyelocytic leukemia." Semin Hematol 31 (1994): 14-7. [PMID: 7831580]
2	Cordoba R, Ramirez E, Lei SH, et al. "Hypercalcemia due to an interaction of all-trans retinoic acid (ATRA) and itraconazole therapy for acute promyelocytic leukemia successfully treated with zoledronic acid." Eur J Clin Pharmacol 64 (2008): 1031-2. [PMID: 18584165]
3	Dixon KS, Hassoun A "Pseudotumor cerebri due to the potentiation of all-trans retinoic acid by voriconazole." J Am Pharm Assoc (2003) 50 (2010): 742-4. [PMID: 21071321]
4	Hameed DA, el-Metwally TH "The effectiveness of retinoic acid treatment in bladder cancer: impact on recurrence, survival and TGFalpha and VEGF as end-point biomarkers." Cancer Biol Ther 7 (2008): 92-100. [PMID: 18347417]
5	Kizaki M, Ueno H, Yamazoe Y, et al "Mechanisms of retinoid resistance in leukemic cells: possible role of cytochrome P450 and P-glycoprotein." Blood 87 (1996): 725-33. [PMID: 8555497]
6	Lotan Y, Lotan R "Prevention of bladder cancer recurrence by retinoic acid-ketoconazole: a promising strategy?" Cancer Biol Ther 7 (2008): 101-2. [PMID: 18347420]
7	Marill J, Cresteil T, Lanotte M, Chabot GG "Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites." Mol Pharmacol 58 (2000): 1341-8. [PMID: 11093772]
8	Moresco G, Martinello F, Souza LC "[Acute renal failure in patient treated with ATRA and amphotericin B: case report]." J Bras Nefrol 33 (2011): 276-81. [PMID: 21789447]
9	Muindi JRF, Young CW, Warrell RP "Clinical pharmacology of all-trans retinoic acid." Leukemia 8 (1994): 1807-12. [PMID: 7967726]
10	Product Information. Vesanoid (tretinoin). Roche Laboratories, Nutley, NJ.
11	Rigas JR, Francis PA, Muindi JR, Kris MG, Huselton C, DeGrazia F, Orazem JP, Young CW, Warrell RP Jr "Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole." J Natl Cancer Inst 85 (1993): 1921-6. [PMID: 8230282]