Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIZX2AHND)
  Drug Name Clotrimazole Drug Info Triazolam Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antifungal Agents Anxiolytics/Sedatives/Hypnotics
  Structure

 Mechanism of Clotrimazole-Triazolam Interaction (Severity Level: Moderate)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Clotrimazole Triazolam
      Mechanism CYP450 3A4 inhibitor 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
  • Decreased metabolism of Triazolam caused by Clotrimazole mediated inhibition of CYP450 enzyme

Recommended Action
      Management Given the potential for significant interaction, the concomitant use of triazolam with clotrimazole or miconazole mucous membrane preparations should be avoided if possible. The same precaution probably applies also to oral midazolam and high dosages of intravenous midazolam. Otherwise, patients should be cautioned about the potential for interaction and monitored for potentially excessive or prolonged CNS and respiratory depression if these agents are used together. alternatively, benzodiazepines that are not metabolized by CYP450 3A4 (e.g., lorazepam, oxazepam, temazepam) may be considered in patients requiring treatment with azole antifungal agents.

References
1 Ahonen J, Olkkola KT, Neuvonen PJ "Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers." Br J Clin Pharmacol 40 (1995): 270-2. [PMID: 8527290]
2 Ahonen J, Olkkola KT, Neuvonen PJ "Lack of effect of antimycotic itraconazole on the pharmacokinetics or pharmacodynamics of temazepam." Ther Drug Monit 18 (1996): 124-7. [PMID: 8721273]
3 Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ "The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin." Eur J Clin Pharmacol 54 (1998): 53-8. [PMID: 9591931]
4 Brown MW, Maldonado AL, Meredith CG, Speeg KV "Effect of ketoconazole on hepatic oxidative drug metabolism." Clin Pharmacol Ther 37 (1985): 290-7. [PMID: 3971653]
5 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]
6 Greenblatt DJ, Vonmoltke LL, Harmatz JS, Harrel LM, Tobias S, Shader RI, Wright CE "Interaction of triazolam and ketoconazole." Lancet 345 (1995): 191. [PMID: 7823684]
7 Neuvonen PJ, Varhe A, Olkkola KT "The effect of ingestion time interval on the interaction between itraconazole and triazolam." Clin Pharmacol Ther 60 (1996): 326-31. [PMID: 8841155]
8 Olkkola KT, Backman JT, Neuvonen PJ "Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole." Clin Pharmacol Ther 55 (1994): 481-5. [PMID: 8181191]
9 Product Information. Halcion (triazolam). Pharmacia and Upjohn, Kalamazoo, MI.
10 Product Information. ORAVIG (miconazole). Strativa Pharmaceuticals, a Division of Par Pharmaceuticals, Inc., Woodcliff Lake, NJ.
11 Product Information. Xanax (alprazolam). Pharmacia and Upjohn, Kalamazoo, MI.
12 Tsunoda SM, Velez RL, vonMoltke LL, Greenblatt DJ "Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole." Clin Pharmacol Ther 66 (1999): 461-71. [PMID: 10579473]
13 Vanakoski J, Mattila MJ, Vainio P, Idanpaanheikkila JJ, Tornwall M "150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects." Int J Clin Pharmacol Ther 33 (1995): 518-23. [PMID: 8520811]
14 Varhe A, Olkkola KT, Neuvonen PJ "Effect of fluconazole dose on the extent of fluconazole-triazolam interaction." Br J Clin Pharmacol 42 (1996): 465-70. [PMID: 8904618]
15 Varhe A, Olkkola KT, Neuvonen PJ "Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism." Br J Clin Pharmacol 41 (1996): 319-23. [PMID: 8730978]
16 Varhe A, Olkkola KT, Neuvonen PJ "Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole." Clin Pharmacol Ther 56 (1994): 601-7. [PMID: 7995001]
17 Vonmoltke LL, Greenblatt DJ, Cotreaubibbo MM, Harmatz JS, Shader RI "Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine." Br J Clin Pharmacol 38 (1994): 23-31. [PMID: 7946933]
18 Vonmoltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, Shader RI "Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents." J Clin Pharmacol 36 (1996): 783-91. [PMID: 8889898]
19 Wrighton SA, Ring BJ "Inhibition of human CYP3A catalyzed 1'-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine." Pharm Res 11 (1994): 921-4. [PMID: 7937537]
20 Yasui N, Kondo T, Otani K, Furukori H, Kaneko S, Ohkubo T, Nagasaki T, Sugawara K "Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam." Psychopharmacology 139 (1998): 269-73. [PMID: 9784084]
21 Greenblatt DJ, Wright CE, vonMoltke LL, Harmatz JS, Ehrenberg BL, Harrel LM, Corbett K, Counihan M, Tobias S, Shader RI "Ketoconazole inhibition of triazolam and alprazolam clearance: Differential kinetic and dynamic consequences." Clin Pharmacol Ther 64 (1998): 237-47. [PMID: 9757147]