PKIS v2.0 A clinical tool for identifying important pharmacokinetic drug-drug interactions
| 1. Accepted major perpetrators | 2. Rejected perpetrators | 3. Unclassifiable | 4. Full table |

modafinil

  • modafinil is a strong inducer of CYP3A.
  • modafinil is neither an inhibitor or inducer of CYP2C9.
  • modafinil has not been evaluated in the literature showing its role of altering the activities of CYP1A2 and CYP2C19.
  • CYP1A2CYP2C9CYP2C19CYP3A
    Strong inducersphenytoin [1]
    rifampicin [2]
    rifampicin [3]
    lopinavir/ritonavir [4]
    rifampicin [5]
    St. John's wort [6]
    carbamazepine [7]
    modafinil [8]
    phenytoin [9]
    rifampicin [10]
    St. John's wort [11]
    No apparent change in clearanceamodiaquine [12]
    aspirin [13]
    omeprazole [14]
    risperidone [15]
    amodiaquine [12]
    darifenacin [a]
    modafinil [16]
    omeprazole [17]
    prednisone [18]
    St John's wort [11]
    amodiaquine [12]
    levonorgestrel [19]
    risperidone [15]
    topiramate [20]
    cimetidine [21]
    echinacea [22]
    finasteride [23]
    fluoxetine [24]
    gatifloxacin [25]
    methylprednisolone [26]
    paroxetine [27]
    pioglitazone [28]
    saw palmetto [29]
    sertraline [30]
    tenofovir [31]
    tipranavir/ritonavir [32]
    venlafaxine [33]
    Not evaluated in the literatureatazanavir
    insulin
    modafinil
    atazanavir
    efavirenz
    5-fluorouracil
    fluoxetine
    imatinib
    isoniazid
    leflunomide
    phenobarbitone
    phenytoin
    ritonavir
    teniposide
    efavirenz [b]
    indomethacin
    modafinil
    oxcarbazepine
    phenobarbitone
    phenytoin
    prednisone
    anastrozole
    atenolol
    atorvastatin
    caffeine
    cyproterone
    ethosuximide
    danazol
    delavirdine [c]
    digoxin
    gemfibrozil
    lapatinib
    metoprolol
    metronidazole
    mifepristone
    norfloxacin
    quinipristin-dalfopristin
    raloxifene
    repaglinide
    valproate

    Footnotes and References

    a.assessment based on product information accessed via the Therapeutic Goods Administration of Australia Product and Consumer Medicines Information website ( https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=PI&q=&r=https://www.ebs.tga.gov.au/ ).
    b.poster found at http://www.klinikum.uni-heidelberg.de/fileadmin/medizinische_klinik/Abteilung_6/pdf/Posterpreis_VKliPha2008_Bayer.pdf
    c.likely to be a major inhibitor based on subjective evaluation (≥ 2-fold AUC increase or ≥ 50% decrease in clearance of in vivo CYP probe).
    1.Wietholtz H, Zysset T, Kreiten K, Kohl D, Buchsel R, Matern S. Effect of phenytoin, carbamazepine, and valproic acid on caffeine metabolism. European Journal of Clinical Pharmacology 1989; 36: 401-06.[PubMed]
    2.Backman JT, Granfors MT, Neuvonen PJ. Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. European Journal of Clinical Pharmacology 2006; 62: 451-61.[PubMed]
    3.Adams M, Pieniaszek HJ, Gammaitoni AR, Ahdieh H. Oxymorphone extended release does not affect CYP2C9 or CYP3A4 metabolic pathways. Journal of Clinical Pharmacology 2005; 45: 337-45.[PubMed]
    4.Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, Eron JJJ, Klein CE, Rublein JC, Kashuba ADM. Lopinavir/Ritonavir Induces the Hepatic Activity of Cytochrome P450 Enzymes CYP2C9, CYP2C19, and CYP1A2 But Inhibits the Hepatic and Intestinal Activity of CYP3A as Measured by a Phenotyping Drug Cocktail in Healthy Volunteers. Journal of Acquired Immune Deficiency Syndromes 2006; 42: 52-60.[PubMed]
    5.Haas CE, Brazeau D, Cloen D, Booker BM, Frerichs V, Zaranek C, Frye RF, Kufel T. Cytochrome P-450 mRNA expression in peripheral blood lymphocytes as a predictor of enzyme induction. European Journal of Clinical Pharmacology 2005; 61: 583-93.[PubMed]
    6.Wang LS, Zhou G, Zhu B, Wu J, Wang JG, El-Aty AMA, Li T, Liu J, Yang TL, Wang D, Zhong XY, Zhou HH. St John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clinical Pharmacology & Therapeutics 2004; 75: 191-97.[PubMed]
    7.Ucar M, Neuvonen M, Luurila H, Dahlqvist R, Neuvonen PJ, Mjorndal T. Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. European Journal of Clinical Pharmacology 2004; 59: 879-82.[PubMed]
    8.Robertson P, Hellriegel ET, Arora S, Nelson M. Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers. Clinical Pharmacology & Therapeutics 2002; 71: 46-56.[PubMed]
    9.Backman JT, Olkkola KT, Ojala M, Laaksovirta H, Neuvonen PJ. Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin. Epilepsia 1996; 37: 253-57.[PubMed]
    10.Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clinical Pharmacology & Therapeutics 1996; 59: 7-13.[PubMed]
    11.Wang ZQ, Gorski C, Hamman MA, Huang SM, Lesko LJ, Hall SD. The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clinical Pharmacology & Therapeutics 2001; 70: 317-26.[PubMed]
    12.Wennerholm A, Nordmark A, Pihlsgard M, Mahindi M, Bertilsson L, Gustafsson LL. Amodiaquine, its desethylated metabolite, or both, inhibit the metabolism of debrisoquine (CYP2D6) and losartan (CYP2C9) in vivo. European Journal of Clinical Pharmacology 2006; 62: 539-46.[PubMed]
    13.Chen XP, Tan ZR, Huang SL, Huang Z, Ou-Yang DS, Zhou HH. Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects. Clinical Pharmacology & Therapeutics 2003; 73: 264-71.[PubMed]
    14.Sarich T, Kalhorn T, AlSayegh F, Adams S, Slattery J, Goldstein J, Nelson S, Wright J. The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin. Clinical Pharmacology & Therapeutics 1997; 62: 21-28.[PubMed]
    15.Eap CB, Bondolfi G, Zullino D, Bryois C, Fuciec M, Savary L, Jonzier-Perey M, Baumann P. Pharmacokinetic drug interaction potential of risperidone with cytochrome P450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test. Therapeutic Drug Monitoring 2001; 23: 228-31.[PubMed]
    16.Robertson P, Hellriegel ET, Arora S, Nelson M. Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers. Journal of Clinical Pharmacology 2002; 42: 205-14.[PubMed]
    17.Bachmann KA, Sullivan TJ, Jauregui L, Reese JH, Miller K, Levine L. Absence of an inhibitory effect of omeprazole and nizatidine on phenytoin disposition, a marker of CYP2C activity. British Journal of Clinical Pharmacology 1993; 36: 380-82.[PubMed]
    18.Breimer DD, Zilly W, Richter E. Influence of corticosteroid on hexobarbital and tolbutamide disposition. Clinical Pharmacology & Therapeutics 1978; 24: 208-12.[PubMed]
    19.Palovaara S, Tybring G, Laine K. The effect of ethinyloestradiol and levonorgestrel on the CYP2C19-mediated metabolism of omeprazole in healthy female subjects. British Journal of Clinical Pharmacology 2003; 56: 232-37.[PubMed]
    20.Sachdeo RC, Sachdeo SK, Levy RH, Streeter AJ, Bishop FE, Kunze KL, Mather GG, Roskos LK, Shen DD, Thummel KE, Trager WF, Curtin CR, Doose DR, Gisclon LG, Bialer M. Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. Epilepsia 2002; 43: 691-96.[PubMed]
    21.Greenblatt DJ, Locniskar A, Scavone JM, Blyden GT, Ochs HR, Harmatz JS, Shader RI. Absence of interaction of cimetidine and ranitidine with intravenous and oral midazolam. Anesthesia and Analgesia 1986; 65: 176-80.[PubMed]
    22.Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M, Hall SD. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clinical Pharmacology & Therapeutics 2004; 75: 89-100.[PubMed]
    23.Yasumori T, Narita H, Matsuda T, Takubo T, Ogawa M, Ishii M, Hara K, Ishii Y, Okuyama K, Fujimoto G, Ochiai H, Kano A, Hasegawa S, Sato K, Taniguchi T. Finasteride 1 mg has no inhibitory effect on omeprazole metabolism in extensive and poor metabolizers for CYP2C19 in Japanese. European Journal of Clinical Pharmacology 2006; 62: 939-46.[PubMed]
    24.Lam YWF, Alfaro CL, Ereshefsky L, Miller M. Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone. Journal of Clinical Pharmacology 2003; 43: 1274-82.[PubMed]
    25.Grasela DM, LaCreta FP, Kollia GD, Randall DM, Uderman HD. Open-label, nonrandomized study of the effects of gatifloxacin on the pharmacokinetics of midazolam in healthy male volunteers. Pharmacotherapy 2000; 20: 330-35.[PubMed]
    26.Villikka K, Varis T, Backman JT, Neuvonen PJ, Kivisto KT. Effect of methylprednisolone on CYP3A4-mediated drug metabolism in vivo. European Journal of Clinical Pharmacology 2001; 57: 457-60.[PubMed]
    27.Calvo G, García-Gea C, Luque A, Morte A, Dal-Ré R, Barbanoj M. Lack of pharmacologic interaction between paroxetine and alprazolam at steady state in healthy volunteers. Journal of Clinical Psychopharmacology 2004; 24: 268-76.[PubMed]
    28.Prueksaritanont T, Vega JM, Zhao J, Gagliano K, Kuznetsova O, Musser B, Amin RD, Liu L, Roadcap BA, Dilzer S, Lasseter KC, Rogers JD. Interactions between simvastatin and troglitazone or pioglitazone in healthy subjects. Journal of Clinical Pharmacology 2001; 41: 573-81.[PubMed]
    29.Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang JS, Chavin KD. Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers. Clinical Pharmacology & Therapeutics 2003; 74: 536-42.[PubMed]
    30.Hassan PC, Sproule BA, Naranjo CA, Herrmann N. Dose-response evaluation of the interaction between sertraline and alprazolam in vivo. Journal of Clinical Psychopharmacology 2000; 20: 150-58.[PubMed]
    31.Abel S, Russell D, Whitlock LA, Ridgway CE, Muirhead GJ. The effects of cotrimoxazole or tenofovir co-administration on the pharmacokinetics of maraviroc in healthy volunteers. British Journal of Clinical Pharmacology 2008; 65: 47-53.[PubMed]
    32.Abel S, Russell D, Taylor-Worth RJ, Ridgway CE, Muirhead GJ. Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers. British Journal of Clinical Pharmacology 2008; 65: 27-37.[PubMed]
    33.DeVane CL, Donovan JL, Liston HL, Markowitz JS, Cheng KT, Risch SC, Willard L. Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers. Journal of Clinical Psychopharmacology 2004; 24: 4-10.[PubMed]
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