Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIGWKE169)
  Drug Name Carbamazepine Drug Info Ethotoin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Anticonvulsants/Antimanic Agents Anticonvulsants
  Structure

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

Recommended Action
      Management Close observation for clinical and laboratory evidence of altered effects is recommended, particularly when one drug is started or discontinued. Patients should be advised to notify their physician if they experience loss of seizure control or symptoms of hydantoin toxicity (drowsiness, visual disturbances, change in mental status, nausea, or ataxia).

References
1 Gratz ES, Theodore WH, Newmark ME, Kupferberg HJ, Porter RJ, Qu Z "Effect of carbamazepine on phenytoin clearance in patients with complex partial seizures." Neurology 32 (1982): a223.
2 Hansen JM, Siersbaek-Nielsen K, Skovsted L "Carbamazepine-induced acceleration of diphenylhydantoin and warfarin metabolism in man." Clin Pharmacol Ther 12 (1971): 539-43. [PMID: 5567804]
3 Morris JC, Dodson E, Hatlelid JM, Ferrendelli JA "Phenytoin and carbamazepine, alone and in combination: anticonvulsant and neurotoxic effects." Neurology 37 (1987): 1111-8. [PMID: 3601077]
4 Perucca E, Richens A "Reversal by phenytoin of carbamazepine-induced water intoxication: a pharmacokinetic interaction." J Neurol Neurosurg Psychiatry 43 (1980): 540-5. [PMID: 7205298]
5 Ramsay RE, McManus DQ, Guterman A, et al "Carbamazepine metabolism in humans: effect of concurrent anticonvulsant therapy." Ther Drug Monit 12 (1990): 235-41. [PMID: 2112276]
6 Zielinski JJ, Haidukewych D "Dual effects of carbamazepine-phenytoin interaction." Ther Drug Monit 9 (1987): 21-3. [PMID: 3576659]
7 Zielinski JJ, Haidukewych D, Leheta BJ "Carbamazepine-phenytoin interaction: elevation of plasma phenytoin concentrations due to carbamazepine comedication." Ther Drug Monit 7 (1985): 51-3. [PMID: 3992622]