Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIDTHQOJ9)
Drug Name			Ethotoin		Drug Info		Anisindione		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Anticonvulsants				Anticoagulants
Structure

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

Drug Name		Ethotoin				Anisindione
Mechanism		CYP450 inducer				CYP450 substrate
Key Mechanism Factor 1
		Factor Name		Cytochrome P450				Structure Sequence
		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 Anisindione caused by Ethotoin mediated induction of CYP450 enzyme

Recommended Action
Management		Phenytoin serum concentrations and INR/PT should be monitored in patients receiving this combination and whenever the dosage is changed or discontinued. Patients should be advised to promptly report any signs of bleeding (e.g., pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, nosebleeds, bleeding of gums from brushing, red or brown urine, or red or black stools) or hydantoin toxicity (e.g., drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia) to their physician.

References
1	Koch-Weser J, Sellers EM "Drug interactions with coumarin anticoagulants (first of two parts)." N Engl J Med 285 (1971): 487-98. [PMID: 4397794]
2	Koch-Weser J, Sellers EM "Drug interactions with coumarin anticoagulants (second of two parts)." N Engl J Med 285 (1971): 547-58. [PMID: 4397794]
3	Nappi JM "Warfarin and phenytoin interaction." Ann Intern Med 90 (1979): 852. [PMID: 434697]