Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDI36VQAT5)
  Drug Name Cyclosporine Drug Info Ethotoin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antiviral Agents Anticonvulsants
  Structure

 Mechanism of Cyclosporine-Ethotoin Interaction (Severity Level: Moderate)
     CYP450 enzyme induction Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Cyclosporine Ethotoin
      Mechanism CYP450 substrate CYP450 inducer
      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 Cyclosporine caused by Ethotoin mediated induction of CYP450 enzyme

Recommended Action
      Management Cyclosporine levels should be closely monitored during concomitant therapy and more frequently when phenytoin is started or stopped. The dosage of cyclosporine should be adjusted to maintain therapeutic concentrations. Some experts suggest that this interaction could persist for a week or more following discontinuation of phenytoin.

References
1 Cerner Multum, Inc. "Australian Product Information.".
2 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
3 Formea CM, Evans CG, Karlix JL "Altered cytochrome p450 metabolism of calcineurin inhibitors: case report and review of the literature." Pharmacotherapy 25 (2005): 1021-9. [PMID: 16006281]
4 Freeman DJ, Laupacis A, Keown PA, et al "Evaluation of cyclosporin-phenytoin interaction with observations on cyclosporin metabolites." Br J Clin Pharmacol 18 (1984): 887-93. [PMID: 6529529]
5 Keown PA, Laupacis A, Carruthers G, et al. "Interaction between phenytoin and cyclosporine following organ transplantation." Transplantation 38 (1984): 304-6. [PMID: 6474556]
6 Keown PA, Stiller CR, Laupacis AL, et al "The effects and side effects of cyclosporine: relationship to drug pharmacokinetics." Transplant Proc 14 (1982): 659-61. [PMID: 6762722]
7 Product Information. Sandimmune (cyclosporine). Sandoz Pharmaceuticals Corporation, East Hanover, NJ.
8 Rowland M, Gupta SK "Cyclosporin-phenytoin interaction: re-evaluation using metabolite data." Br J Clin Pharmacol 24 (1987): 329-34. [PMID: 3663449]
9 Schmidt H, Naumann R, Jaschonek K, Einsele H, Dopfer R, Ehninger G "Drug interaction between cyclosporin and phenytoin in allogeneic bone marrow transplantation." Bone Marrow Transplant 4 (1989): 212-3. [PMID: 2650795]
10 Schweitzer EJ, Canafax DM, Gillingham KJ, Najarian JS, Matas AJ "Phenytoin administration in kidney recipients on csa immunosuppression." J Am Soc Nephrol 2 (1991): 816.
11 Yee GC, McGuire TR "Pharmacokinetic drug interactions with cyclosporin (Part I)." Clin Pharmacokinet 19 (1990): 319-32. [PMID: 2208899]