Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIV3R86P0)
  Drug Name Selegiline Drug Info Norgestrel Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Dopaminergic Antiparkinsonism Agents/Mao Inhibitors Contraceptive Agents
  Structure

 Mechanism of Selegiline-Norgestrel Interaction (Severity Level: Moderate)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Selegiline Norgestrel
      Mechanism CYP450 3A substrate CYP450 3A inhibitor
      Key Mechanism Factor 1
Factor Name Cytochrome P450 3A 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 Selegiline caused by Norgestrel mediated inhibition of CYP450 enzyme

Recommended Action
      Management Monitoring for signs and symptoms of selegiline toxicity such as excessive MAO inhibition and hypertension when female sex steroids are added and monitoring for reduced selegiline effectiveness when steroids are withdrawn is recommended. Selegiline dosage and dietary adjustments (avoiding tyramine) may be required. Patients should be advised to notify their physician promptly if they experience symptoms such as severe headache, dizziness, nervousness, weakness, irritability, altered consciousness, seizures, confusion, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, or tachycardia.

References
1 Laine K, Anttila M, Helminen A, Karnani H, Huupponen R "Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids." Br J Clin Pharmacol 47 (1999): 249-54. [PMID: 10215747]