Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI2ZQL5BX)
Drug Name			Mephenytoin		Drug Info		Methsuximide		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Anticonvulsants				Anticonvulsants
Structure

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

Drug Name		Mephenytoin				Methsuximide
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 Methsuximide caused by Mephenytoin mediated induction of CYP450 enzyme

Recommended Action
Management		If a succinimide and a hydantoin must be used together, close observation for evidence of altered hydantoin effect is recommended. Patients should be advised to notify their physician if they experience symptoms of possible hydantoin toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia.

References
1	Browne TR, Feldman RG, Buchanan RA, et al. "Methsuximide for complex partial seizures: efficacy, toxicity, clinical pharmacology, and drug interactions." Neurology 33 (1983): 414-8. [PMID: 6403891]
2	Giaccone M, Bartoli A, Gatti G, Marchiselli R, Pisani F, Latella MA, Perucca E "Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients." Br J Clin Pharmacol 41 (1996): 575-9. [PMID: 8799524]
3	Gilman AG, Rall TW, Nies AS, Taylor P, eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 8th ed." New York, NY: Pergamon Press Inc. (1990):.
4	Mendez JS, Cotzias GC, Mena I, Papavasiliou PS "Diphenylhydantoin: blocking of levodopa effects." Arch Neurol 32 (1975): 44-6. [PMID: 123156]
5	Rambeck B "Pharmacological interactions of mesuximide with phenobarbital and phenytoin in hospitalized epileptic patients." Epilepsia 20 (1979): 147-56. [PMID: 110583]