Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIBPMTF46)
Drug Name			Betamethasone		Drug Info		Ethotoin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiinflammatory Agents				Anticonvulsants
Structure

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

Drug Name		Betamethasone				Ethotoin
Mechanism		CYP450 3A4 substrate				CYP450 3A4 inducer
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 Betamethasone caused by Ethotoin mediated induction of CYP450 enzyme

Recommended Action
Management		Patients should be closely monitored for clinical and laboratory evidence of reduced corticosteroid effects and changes in phenytoin concentrations during concomitant therapy. Some patients may require increased corticosteroid dosages.

References
1	Frey BM, Frey FJ "Phenytoin modulates the pharmacokinetics of prednisolone and the pharmacodynamics of prednisolone as assessed by the inhibition of the mixed lymphocyte reaction in humans." Eur J Clin Invest 14 (1984): 1-6. [PMID: 6230241]
2	Haque N, Thrasher K, Werk EE, Jr Knowles HC, Jr Sholiton LJ "Studies on dexamethasone metabolism in man: effect of diphenylhydantoin." J Clin Endocrinol Metab 34 (1972): 44-50. [PMID: 5008232]
3	Lackner TE "Interaction of dexamethasone with phenytoin." Pharmacotherapy 11 (1991): 344-7. [PMID: 1923918]
4	Lawson LA, Blouin RA, Smith RB, Rapp RP, Young AB "Phenytoin-dexamethasone interaction: a previously unreported observation." Surg Neurol 16 (1981): 23-4. [PMID: 7280966]
5	Stjernholm MR, Katz FH "Effects of diphenylhydantoin, phenobarbital, and diazepam on the metabolism of methylprednisolone and its sodium succinate." J Clin Endocrinol Metab 41 (1975): 887-93. [PMID: 1184723]
6	Wong DD, Longenecker RG, Liepman M, Baker S, LaVergne M "Phenytoin-dexamethasone: a possible drug-drug interaction." JAMA 254 (1985): 2062-3. [PMID: 4046133]