Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDI1FCB5IU)
  Drug Name Cisapride Drug Info Simvastatin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Gastrointestinal Agents Statins/Antihyperlipidemic Agents
  Structure

 Mechanism of Cisapride-Simvastatin Interaction (Severity Level: Moderate)
     Altered gastrointestinal dynamics Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Cisapride Simvastatin
      Mechanism 1 Increase gastrointestinal motility Absorption is influenced by gastrointestinal motility
      Key Mechanism Factor 1
Factor Name Gastrointestinal Motility
Factor Description Gastrointestinal motility is an important factor in determining the absorption of orally administered drugs, and it controls the residence time of the drug in the digestive tract.
      Mechanism Description
  • Altered absorption of Simvastatin due to GI dynamics variation caused by Cisapride 
     Competitive inhibition of metabolic enzyme Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Cisapride Simvastatin
      Mechanism 2 CYP450 3A4 substrate CYP450 3A4 substrate
      Key Mechanism Factor 2
Factor Name Cytochrome P450 3A4
×
Structure Sequence
MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFDMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIAEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSMDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVFPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSIIFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVNETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFSKKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGGLLQPEKPVVLKVESRDGTVSGA
Gene Name CYP3A4
Uniprot ID CP3A4_HUMAN
KEGG Pathway hsa:1576
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 plasma concentrations of Cisapride and Simvastatin due to competitive inhibition of the same metabolic pathway

Recommended Action
      Management Due to the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of cisapride, an HMG-CoA reductase inhibitor that is not metabolized by CYP450 3A4 such as fluvastatin or pravastatin may be preferable in patients receiving concomitant therapy with cisapride. If simvastatin must be used, clinicians should monitor patients for cisapride toxicity as well as reduced cholesterol-lowering effects of simvastatin. Patients should be advised to seek medical attention if they experience fainting, dizziness, an irregular heartbeat or pulse, or other unusual symptoms while using cisapride.

References
1 Product Information. Propulsid (cisapride). Janssen Pharmaceutica, Titusville, NJ.
2 Simard C, OHara GE, Prevost J, Guilbaud R, Masse R, Turgeon J "Study of the drug-drug interaction between simvastatin and cisapride in man." Eur J Clin Pharmacol 57 (2001): 229-34. [PMID: 11497338]