Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDISAVBOJ5)
  Drug Name St. John's Wort Drug Info Maraviroc Drug Info
  Drug Type Natural product Small molecule
  Therapeutic Class Herbal Products/Antidepressants Anti-Hiv Agents

 Mechanism of St. John's Wort-Maraviroc Interaction (Severity Level: Major)
     CYP450 enzyme induction Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name St. John's Wort Maraviroc
      Mechanism CYP450 3A4 inducer CYP450 3A4 substrate
      Key Mechanism Factor 1
Factor Name Cytochrome P450 3A4
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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 metabolism of Maraviroc caused by St. John's Wort mediated induction of CYP450 enzyme

Recommended Action
      Management Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, patients treated with antiretroviral agents should avoid using St. John's wort. Patients should be advised to consult with their caregivers before using any herbal or alternative medicines.

References
1 Acosta EP, Henry K, Baken L, Page LM, Fletcher CV "Indinavir concentrations and antiviral effect." Pharmacotherapy 19 (1999): 708-12. [PMID: 10391416]
2 de Maat MM, Hoetelmans RM, Mathot RA, et al "Drug interaction between St John's wort and nevirapine." AIDS 15 (2001): 420-1. [PMID: 11273226]
3 Durr D, Stieger B, KullakUblick GA, Rentsch KM, Steinert HC, Meier PJ, Fattinger K "St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4." Clin Pharmacol Ther 68 (2000): 598-604. [PMID: 11180019]
4 FDA "FDA public health advisory on risk of drug interactions with St John's wort and indinavir and other drugs.".
5 Izzo AA, Ernst E "Interactions between herbal medicines and prescribed drugs: a systematic review." Drugs 61 (2001): 2163-75. [PMID: 11772128]
6 Mangum EM, Graham KK "Lopinavir-Ritonavir: a new protease inhibitor." Pharmacotherapy 21 (2001): 1352-63. [PMID: 11714208]
7 Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J "Indinavir concentrations and St John's wort." Lancet 355 (2000): 547-8. [PMID: 10683007]
8 Product Information. Agenerase (amprenavir). Glaxo Wellcome, Research Triangle Pk, NC.
9 Product Information. Aptivus (tipranavir). Boehringer-Ingelheim, Ridgefield, CT.
10 Product Information. Crixivan (indinavir). Merck & Co, Inc, West Point, PA.
11 Product Information. Fortovase (saquinavir) Roche Laboratories, Nutley, NJ.
12 Product Information. Kaletra (lopinavir-ritonavir) Abbott Pharmaceutical, Abbott Park, IL.
13 Product Information. Lexiva (fosamprenavir). GlaxoSmithKline, Research Triangle Park, NC.
14 Product Information. Norvir (ritonavir). Abbott Pharmaceutical, Abbott Park, IL.
15 Product Information. Prezista (darunavir). Ortho Biotech Inc, Bridgewater, NJ.
16 Product Information. Reyataz (atazanavir). Bristol-Myers Squibb, Princeton, NJ.
17 Product Information. Selzentry (maraviroc). Pfizer U.S. Pharmaceuticals Group, New York, NY.
18 Product Information. Viracept (nelfinavir). Agouron Pharma Inc, La Jolla, CA.
19 Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH "St John's Wort: Effect on CYP3A4 activity." Clin Pharmacol Ther 67 (2000): 451-7. [PMID: 10824623]
20 Veldkamp AI, Weverling GJ, Lange JM, et al. "High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals." AIDS 15 (2001): 1089-95. [PMID: 11416710]
21 Durant J, Clevenbergh P, Garraffo R, Halfon P, Icard S, DelGiudice P, Montagne N, Schapiro JM, Dellamonica P "Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study." Aids 14 (2000): 1333-9. [PMID: 10930147]