Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIKH3CY79)
  Drug Name Cimetidine Drug Info Propranolol Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antiulcer Agents Antianxiety Agents
  Structure

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

Recommended Action
      Management Clinical monitoring of patient response and tolerance is recommended when cimetidine is added to or discontinued from a beta-blocker regimen.

References
1 Asgharnejad M, Powell R, Donn K, Danis M "The effect of cimetidine dose timing on oral propranolol kinetics in adults." Clin Pharmacol Ther 41 (1987): 203. [PMID: 3392231]
2 Daneshmend TK, Roberts CJ "The effects of enzyme induction and enzyme inhibition on labetalol pharmacokinetics." Br J Clin Pharmacol 18 (1984): 393-400. [PMID: 6487478]
3 Duchin KL, Stern MA, Willard DA, McKinstry DN "Comparison of kinetic interactions of nadolol and propranolol with cimetidine." Am Heart J 108 (1984): 1084-6. [PMID: 6148867]
4 Duchin KL, Stern MA, Willard DA, McKinstry DN "Kinetic interactions of nadolol and propranolol with cimetidine." Br J Clin Pharmacol 17 (1984): 486-7. [PMID: 6721996]
5 Durant PA, Joucken K "Bronchospasm and hypotension during cardiopulmonary bypass after preoperative cimetidine and labetalol therapy." Br J Anaesth 56 (1984): 917-20. [PMID: 6743454]
6 Feely J, Wilkinson GR, Wood AJ "Reduction of liver blood flow and propranolol metabolism by cimetidine." N Engl J Med 304 (1981): 692-5. [PMID: 7464861]
7 Hardman JG, Gilman AG, Limbird LE eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 9th ed." New York, NY: McGraw-Hill (1995):.
8 Houtzagers JJ, Streurman O, Regardh CG "The effect of pretreatment with cimetidine on the bioavailability and disposition of atenolol and metoprolol." Br J Clin Pharmacol 14 (1982): 67-72. [PMID: 6125199]
9 Ishii Y, Nakamura K, Tsutsumi K, Kotegawa T, Nakano S, Nakatsuka K "Drug interaction between cimetidine and timolol ophthalmic solution: Effect on heart rate and intraocular pressure in healthy Japanese volunteers." J Clin Pharmacol 40 (2000): 193-9. [PMID: 10664926]
10 Kirch W, Rose I, Klingmann I, Pabst J, Ohnhaus EE "Interaction of bisoprolol with cimetidine and rifampicin." Eur J Clin Pharmacol 31 (1986): 59-62. [PMID: 2877885]
11 Kirch W, Spahn H, Kohler H, et al "Interaction of metoprolol, propranolol and atenolol with concurrent administration of cimetidine." Klin Wochenschr 60 (1982): 1401-7. [PMID: 7176462]
12 Product Information. Betapace (sotalol). Berlex, Richmond, CA.
13 Product Information. Cartrol (carteolol). Abbott Pharmaceutical, Abbott Park, IL.
14 Product Information. Corgard (nadolol). Bristol-Myers Squibb, Princeton, NJ.
15 Product Information. Tenormin (atenolol). ICN Pharmaceuticals Inc, Cost Mesa, CA.
16 Rey E, Jammet P, d'Athis P, et al "Effect of cimetidine on the pharmacokinetics of the new beta-blocker betaxolol." Arzneimittelforschung 37 (1987): 953-6. [PMID: 2890358]
17 Desmedt S, Spinewine A, Jadoul M, Henrard S, Wouters D, Dalleur O. Impact of a clinical decision support system for drug dosage in patients with renal failure.?Int J Clin Pharm. 2018;40(5):1225-1233. [PMID: 29785684]
18 Somogyi AA, Bochner F, Sallustio BC "Stereoselective inhibition of pindolol renal clearance by cimetidine in humans." Clin Pharmacol Ther 51 (1992): 379-87. [PMID: 1563208]
19 Spahn H, Kirch W, Hajdu P, et al "Penbutolol pharmacokinetics: the influence of concomitant administration of cimetidine." Eur J Clin Pharmacol 29 (1986): 555-60. [PMID: 3956561]
20 Toon S, Davidson EM, Garstang FM, et al "The racemic metoprolol H2-antagonist interaction." Clin Pharmacol Ther 43 (1988): 283-9. [PMID: 3345620]