Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIOE1GMQT)
  Drug Name Disulfiram Drug Info Fosphenytoin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Alcohol Deterrents Anticonvulsants
  Structure

 Mechanism of Disulfiram-Fosphenytoin Interaction (Severity Level: Moderate)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Disulfiram Fosphenytoin
      Mechanism CYP450 inhibitor 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
  • Decreased metabolism of Fosphenytoin caused by Disulfiram mediated inhibition of CYP450 enzyme

Recommended Action
      Management Patients should be closely observed for signs of hydantoin toxicity if these drugs must be given concurrently and serum phenytoin concentrations should be monitored. Patients should be advised to notify their physician if they experience symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia. The hydantoin dose may need to be decreased. In addition, the dose of the hydantoin may require adjustment when initiating or discontinuing treatment with disulfiram. Recovery may take two to three weeks after treatment with disulfiram is discontinued.

References
1 Brown CG, Kaminsky MJ, Feroli ER, Gurley HT "Delirium with phenytoin and disulfiram administration." Ann Emerg Med 12 (1983): 310-3. [PMID: 6625283]
2 Cerner Multum, Inc. "Australian Product Information.".
3 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
4 Kiorboe E "Phenytoin intoxication during treatment with antabuse (disulfiram)." Epilepsia 7 (1966): 246-9. [PMID: 5332920]
5 Olesen OV "Disulfiram (antabuse) as inhibitor of phenytoin metabolism." Acta Pharmacol Toxicol (Copenh) 24 (1966): 317-22. [PMID: 6013115]
6 Taylor JW, Alexander B, Lyon LW "Mathematical analysis of a phenytoin-disulfiram interaction." Am J Hosp Pharm 38 (1981): 93-5. [PMID: 7211876]