Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIIUG0SQF)
  Drug Name Cisapride Drug Info Saquinavir Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Gastrointestinal Agents Anti-Hiv Agents
  Structure

 Mechanism of Cisapride-Saquinavir Interaction (Severity Level: Major)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Cisapride Saquinavir
      Mechanism CYP450 3A4 substrate CYP450 3A4 inhibitor
      Key Mechanism Factor 1
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
  • Decreased metabolism of Cisapride caused by Saquinavir mediated inhibition of CYP450 enzyme

Recommended Action
      Management Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of cisapride, concomitant use with protease inhibitors is considered contraindicated.

References
1 Bran S, Murray WA, Hirsch IB, Palmer JP "Long QT syndrome during high-dose cisapride." Arch Intern Med 155 (1995): 765-8. [PMID: 7695465]
2 Desta Z, Soukhova N, Mahal SK, Flockhart DA "Interaction of cisapride with the human cytochrome P450 system: metabolism and inhibition studies." Drug Metab Dispos 28 (2000): 789-800. [PMID: 10859153]
3 Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57. [PMID: 10668858]
4 Gill J, Feinberg J "Saquinavir soft gelatin capsule - A comparative safety review." Drug Safety 24 (2001): 223-32. [PMID: 11347724]
5 Gray VS "Syncopal episodes associated with cisapride and concurrent drugs." Ann Pharmacother 32 (1998): 648-51. [PMID: 9640482]
6 Hill SL, Evangelista JK, Pizzi AM, Mobassaleh M, Fulton DR, Berul CI "Proarrhythmia associated with cisapride in children." Pediatrics 101 (1998): 1053-6. [PMID: 9606235]
7 Lewin MB, Bryant RM, Fenrich AL, Grifka RG "Cisapride-induced long QT interval." J Pediatr 128 (1996): 279-81. [PMID: 8636830]
8 Malaty LI, Kuper JJ "Drug interactions of HIV protease inhibitors." Drug Safety 20 (1999): 147-69. [PMID: 10082072]
9 Mangum EM, Graham KK "Lopinavir-Ritonavir: a new protease inhibitor." Pharmacotherapy 21 (2001): 1352-63. [PMID: 11714208]
10 Michalets EL "Update: clinically significant cytochrome P-450 drug interactions." Pharmacotherapy 18 (1998): 84-112. [PMID: 9469685]
11 Michalets EL, Williams CR "Drug interactions with cisapride: clinical implications." Clin Pharmacokinet 39 (2000): 49-75. [PMID: 10926350]
12 Product Information. Agenerase (amprenavir). Glaxo Wellcome, Research Triangle Pk, NC.
13 Product Information. Crixivan (indinavir). Merck & Co, Inc, West Point, PA.
14 Product Information. Fortovase (saquinavir) Roche Laboratories, Nutley, NJ.
15 Product Information. Incivek (telaprevir). Vertex Pharmaceuticals, Cambridge, MA.
16 Product Information. Lexiva (fosamprenavir). GlaxoSmithKline, Research Triangle Park, NC.
17 Product Information. Norvir (ritonavir). Abbott Pharmaceutical, Abbott Park, IL.
18 Product Information. Prezista (darunavir). Ortho Biotech Inc, Bridgewater, NJ.
19 Product Information. Propulsid (cisapride). Janssen Pharmaceutica, Titusville, NJ.
20 Product Information. Reyataz (atazanavir). Bristol-Myers Squibb, Princeton, NJ.
21 Product Information. Victrelis (boceprevir). Schering-Plough Corporation, Kenilworth, NJ.
22 Product Information. Viracept (nelfinavir). Agouron Pharma Inc, La Jolla, CA.