Clinical Pharmacokinetics

, Volume 38, Issue 1, pp 41–57 | Cite as

Pharmacokinetic-Pharmacodynamic Consequences and Clinical Relevance of Cytochrome P450 3A4 Inhibition

  • George K. Dresser
  • J. David Spence
  • David G. BaileyEmail author
Review Article Drug Interactions


Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein.

Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme Areductase inhibitors (‘statins’) and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor.

Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir.

The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age.

Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.


Itraconazole Ritonavir Felodipine Cisapride Terfenadine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism [review]. Annu Rev Pharmacol Toxicol 1999; 39: 1–17.PubMedCrossRefGoogle Scholar
  2. 2.
    Kolars JC, Lown KS, Schmiedlin-Ren P, et al. CYP3A gene expression in human gut epithelium. Pharmacogenetics 1994; 4: 247–59.PubMedCrossRefGoogle Scholar
  3. 3.
    Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans [review]. J Pharmacokinet Biopharm 1996; 24: 475–90.PubMedGoogle Scholar
  4. 4.
    Anttila S, Hukkanen J, Hakkola J, et al. Expression and localization of CYP3A4 and CYP3A5 in human lung. Am J Respir Cell Mol Biol 1997; 16: 242–9.PubMedGoogle Scholar
  5. 5.
    Lown KS, Kolars JC, Thummel KE, et al. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. Drug Metab Dispos 1994; 22: 947–55.PubMedGoogle Scholar
  6. 6.
    Tanaka E. In vivo age-related changes in hepatic drug-oxidizing capacity in humans [review]. J Clin Pharm Ther 1998; 23: 247–55.PubMedCrossRefGoogle Scholar
  7. 7.
    Paintaud G, Bechtel Y, Brientini MP, et al. Effects of liver diseases on drug metabolism [review]. Therapie 1996; 51: 384–9.PubMedGoogle Scholar
  8. 8.
    Iqbal S, Vickers C, Elias E. Drug metabolism in end-stage liver disease. In vitro activities of some phase I and phase II enzymes. J Hepatol 1990; 11: 37–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Kashuba AD, Bertino JSJ, Rocci MLJ, et al. Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam. Clin Pharmacol Ther 1998; 64: 269–77.PubMedCrossRefGoogle Scholar
  10. 10.
    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414–23.PubMedGoogle Scholar
  11. 11.
    Landahl S, Edgar B, Gabrielsson M, et al. Pharmacokinetics and blood pressure effects of felodipine in elderly hypertensive patients: a comparison with young healthy subjects. Clin Pharmacokinet 1988; 14: 374–83.PubMedCrossRefGoogle Scholar
  12. 12.
    Lundahl J, Regardh CG, Edgar B, et al. Effects of grapefruit juice ingestion-pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol 1997; 52: 139–45.PubMedCrossRefGoogle Scholar
  13. 13.
    Bailey DG, Malcolm J, Arnold O, et al. Grapefruit juice-drug interactions [review]. Br J Clin Pharmacol 1998; 46: 101–10.PubMedCrossRefGoogle Scholar
  14. 14.
    Greenblatt DJ, Wright CE, von Moltke LL, et al. Ketoconazole inhibition of triazolam and alprazolam clearance: differential kinetic and dynamic consequences. Clin Pharmacol Ther 1998; 64: 237–47.PubMedCrossRefGoogle Scholar
  15. 15.
    Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996; 60: 54–61.PubMedCrossRefGoogle Scholar
  16. 16.
    Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Schinkel AH. Pharmacological insights from P-glycoprotein knockout mice [review]. Int J Clin Pharmacol Ther 1998; 36: 9–13.PubMedGoogle Scholar
  18. 18.
    Kim RB, Wandel C, Leake B, et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999; 16: 408–14.PubMedCrossRefGoogle Scholar
  19. 19.
    Wandel C, Kim RB, Kajiji S, et al. P-glycoprotein and cytochrome P-450 3 A inhibition: dissociation of inhibitory potencies. Cancer Res 1999; 59: 3944–8.PubMedGoogle Scholar
  20. 20.
    Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A [review]. Annu Rev Pharmacol Toxicol 1998; 38: 389–430.PubMedCrossRefGoogle Scholar
  21. 21.
    Lin JH, Lu AY. Inhibition and induction of cytochrome P450 and the clinical implications [review]. Clin Pharmacokinet 1998; 35: 361–90.PubMedCrossRefGoogle Scholar
  22. 22.
    Silverman RB. Mechanism-based enzyme inactivators. Methods Enzymol 1995; 249: 240–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Edwards DJ, Bellevue FH, Woster PM. Identification of 6′,7′-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos 1996; 24: 1287–90.PubMedGoogle Scholar
  24. 24.
    Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, et al. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos 1997; 25: 1228–33.PubMedGoogle Scholar
  25. 25.
    Guengerich FP. Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chem Res Toxicol 1990; 3: 363–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99: 2545–53.PubMedCrossRefGoogle Scholar
  27. 27.
    Ahonen J, Olkkola KT, Neuvonen PJ. Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. Eur J Clin Pharmacol 1997; 5: 415–9.CrossRefGoogle Scholar
  28. 28.
    Monahan BP, Ferguson CL, Killeavy ES, et al. Torsades de pointes occurring in association with terfenadine use. JAMA 1990; 264: 2788–90.PubMedCrossRefGoogle Scholar
  29. 29.
    Tsai WC, Tsai LM, Chen JH. Combined use of astemizole and ketoconazole resulting in torsade de pointes. J Formos Med Assoc 1997; 96: 144–6.PubMedGoogle Scholar
  30. 30.
    Rampe D, Roy ML, Dennis A, et al. A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. FEBS Lett 1997; 417: 28–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Desta Z, Kerbusch T, Flockhart DA. Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Clin Pharmacol Ther 1999; 65: 10–20.PubMedCrossRefGoogle Scholar
  32. 32.
    Zimmermann M, Duruz H, Guinand O, et al. Torsades de Pointes after treatment with terfenadine and ketoconazole. Eur Heart J 1992; 13: 1002–3.PubMedGoogle Scholar
  33. 33.
    Crane JK, Shih HT. Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine. Am J Med 1993; 95: 445–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Pohjola-Sintonen S, Viitasalo M, Toivonene L, et al. Torsades de pointes after terfenadine-itraconazole interaction [published erratum in BMJ 1993 Feb 6; 306 (6874): 374]. BMJ 1993; 306: 186.PubMedCrossRefGoogle Scholar
  35. 35.
    Nattel S, Talajic M, Beaudoin D, et al. Absence of pharmacokinetic interaction between amiodarone and lidocaine. Am J Cardiol 1994; 73: 92–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Paris DG, Parente TF, Bruschetta HR, et al. Torsades de pointes induced by erythromycin and terfenadine [review]. Am J Emerg Med 1994; 12: 636–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Hsieh MH, Chen SA, Chiang CE, et al. Drug-induced torsades de pointes in one patient with congenital long QT syndrome. Int J Cardiol 1996; 54: 85–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Pratt CM, Ruberg S, Morganroth J, et al. Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability. Am Heart J 1996; 131: 472–80.PubMedCrossRefGoogle Scholar
  39. 39.
    Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia [letter]. N Engl J Med 1996; 335: 290–1.PubMedCrossRefGoogle Scholar
  40. 40.
    Katapadi K, Kostandy G, Katapadi M, et al. A review of erythromycin-induced malignant tachyarrhythmia: torsade de pointes. A case report. Angiology 1997; 48: 821–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Sekkarie MA. Torsades de pointes in two chronic renal failure patients treated with cisapride and clarithromycin. Am J Kidney Dis 1997; 30: 437–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Spence JD. Drug interactions with grapefruit: whose responsibility is it to warn the public? Clin Pharmacol Ther 1997; 61: 395–400.PubMedCrossRefGoogle Scholar
  43. 43.
    Thomas AR, Chan LN, Bauman JL, et al. Prolongation of the QT interval related to cisapride-diltiazem interaction. Pharmacotherapy 1998; 18: 381–5.PubMedGoogle Scholar
  44. 44.
    Piquette RK. Torsade de pointes induced by cisapride/clarithromycin interaction. Ann Pharmacother 1999; 33: 22–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Honig PK, Woosley RL, Zamani K, et al. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992; 52: 231–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA 1993; 269: 1513–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Benton RE, Honig PK, Zamani K, et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram. Clin Pharmacol Ther 1996; 59: 383–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Honig PK, Wortham DC, Hull R, et al. Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics. J Clin Pharmacol 1993; 33: 1201–6.PubMedGoogle Scholar
  49. 49.
    Honig PK, Wortham DC, Lazarev A, et al. Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine. J Clin Pharmacol 1996; 36: 345–51.PubMedGoogle Scholar
  50. 50.
    Rau SE, Bend JR, Arnold MO, et al. Grapefruit juice-terfenadine single-dose interaction: magnitude, mechanism, and relevance. Clin Pharmacol Ther 1997; 61: 401–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Clifford CP, Adams DA, Murray S, et al. The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice. Eur J Clin Pharmacol 1997; 52: 311–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Gross AS, Goh YD, Addison RS, et al. Influence of grapefruit juice on cisapride pharmacokinetics. Clin Pharmacol Ther 1999; 65: 395–401.PubMedCrossRefGoogle Scholar
  53. 53.
    Gonzalez MA, Estes KS. Pharmacokinetic overview of oral second-generation HI antihistamines [review]. Int J Clin Pharmacol Ther 1998; 36: 292–300.PubMedGoogle Scholar
  54. 54.
    Markham A, Wagstaff AJ. Fexofenadine [review]. Drugs 1998; 55: 269–74.PubMedCrossRefGoogle Scholar
  55. 55.
    Honig PK, Worham DC, Zamani K, et al. The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans. Clin Pharmacol Ther 1993; 53: 630–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Canafax DM, Graves NM, Hilligoss DM, et al. Interaction between cyclosporine and fluconazole in renal allograft recipients. Transplantation 1991; 51: 1014–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Baciewicz AM, Baciewicz Jr FA. Ketoconazole and fluconazole drug interactions [see comments] [review]. Arch Intern Med 1993; 153: 1970–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Lopez-Gil JA. Fluconazole-cyclosporine interaction: a dose-dependent effect? Ann Pharmacother 1993; 27: 427–30.PubMedGoogle Scholar
  59. 59.
    Assan R, Fredj G, Larger E, et al. FK 506/fluconazole interaction enhances FK 506 nephrotoxicity. Diabete Metab 1994; 20: 49–52.PubMedGoogle Scholar
  60. 60.
    Harris S, Hilligoss DM, Colangelo PM, et al. Azithromycin and terfenadine: lack of drug interaction. Clin Pharmacol Ther 1995; 58: 310–5.PubMedCrossRefGoogle Scholar
  61. 61.
    Ayanian JZ, Fuchs CS, Stone RM. Lovastatin and rhabdomyolysis [letter]. Ann Intern Med 1988; 109: 682–3.PubMedGoogle Scholar
  62. 62.
    Corpier CL, Jones PH, Suki WN, et al. Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients. JAMA 1988; 260: 239–41.PubMedCrossRefGoogle Scholar
  63. 63.
    Biesenbach G, Janko O, Stuby U, et al. Myoglobinuric renal failure due to long-standing lovastatin therapy in a patient with pre-existing chronic renal insufficiency. Nephrol Dial Transplant 1996; 11: 2059–60.PubMedCrossRefGoogle Scholar
  64. 64.
    Hino I, Akama H, Furuya T, et al. Pravastatin-induced rhabdomyolysis in a patient with mixed connective tissue disease. Arthritis Rheum 1996; 39: 1259–60.PubMedCrossRefGoogle Scholar
  65. 65.
    Christians U, Jacobsen W, Floren LC. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar? [review]. Pharmacol Ther 1998; 80: 1–34.PubMedCrossRefGoogle Scholar
  66. 66.
    Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66: 118–27.PubMedGoogle Scholar
  67. 67.
    Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58–65.PubMedCrossRefGoogle Scholar
  68. 68.
    Donahue S, Lachman L, Norton J, et al. Mibefradil significantly increases serum concentrations of atorvastatin but not pravastatin [abstract]. Clin Pharmacol Ther 1999; 65: 179.Google Scholar
  69. 69.
    Muck W, Mai I, Fritsche L, et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 1999; 65: 251–61.PubMedCrossRefGoogle Scholar
  70. 70.
    Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46: 49–53.PubMedCrossRefGoogle Scholar
  71. 71.
    Olbricht C, Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporinetreated kidney graft patients after multiple doses. Clin Pharmacol Ther 1997; 62: 311–21.PubMedCrossRefGoogle Scholar
  72. 72.
    Azie NE, Brater DC, Becker PA, et al. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998; 64: 369–77.PubMedCrossRefGoogle Scholar
  73. 73.
    Donahue S, Lachman L, Norton J, et al. Verapamil significantly increases serum concentrations of simvastatin but not pravastatin [abstract]. Clin Pharmacol Ther 1999; 65: 179.Google Scholar
  74. 74.
    Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998; 64: 477–83.PubMedCrossRefGoogle Scholar
  75. 75.
    Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998; 64: 177–82.PubMedCrossRefGoogle Scholar
  76. 76.
    Liedholm H, Nordin G. Erythromycin-felodipine interaction [letter]. DICP 1991; 25: 1007–8.PubMedGoogle Scholar
  77. 77.
    Neuvonen PJ, Suhonen R. Itraconazole interacts with felodipine. J Am Acad Dermatol 1995; 33: 134–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Tailor SA, Gupta AK, Walker SE, et al. Peripheral edema due to nifedipine-itraconazole interaction: a case report [letter]. Arch Dermatol 1996; 132: 350–2.PubMedCrossRefGoogle Scholar
  79. 79.
    Josefsson M, Zackrisson AL, Ahlner J. Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers. Eur J Clin Pharmacol 1996; 51: 189–93.PubMedCrossRefGoogle Scholar
  80. 80.
    Vincent JC, Foulds G, Dogolo LC, et al. Grapefruit juice does not alter the pharmacokinetics of amlodipine in man [abstract]. Clin Pharmacol Ther 1999; 61: 233.Google Scholar
  81. 81.
    Madsen JK, Jensen JD, Jensen LW, et al. Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine. Eur J Clin Pharmacol 1996; 50: 203–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Bailey DG, Bend JR, Arnold JM, et al. Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice. Clin Pharmacol Ther 1996; 60: 25–33.PubMedCrossRefGoogle Scholar
  83. 83.
    Dresser GK, Bailey DG, Carruthers SG. Grapefruit juice-felodipine interaction in healthy seniors [abstract]. Clin Pharmacol Ther 1999; 65: 192.CrossRefGoogle Scholar
  84. 84.
    Bailey DG, Arnold JM, Munoz C, et al. Grapefruit juice-felodipine interaction: mechanism, predictability, and effect of naringin. Clin Pharmacol Ther 1993; 53: 637–42.PubMedCrossRefGoogle Scholar
  85. 85.
    Bailey DG, Spence JD, Munoz C, et al. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991; 337: 268–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Edgar B, Bailey D, Bergstrand R, et al. Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine and its potential clinical relevance. Eur J Clin Pharmacol 1992; 42: 313–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Lundahl J, Regardh CG, Edgar B, et al. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. Eur J Clin Pharmacol 1995; 49: 61–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma concentrations and effects of felodipine. Clin Pharmacol Ther 1997; 61: 410–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Uno T, Ohkubo T, Sugawara K, et al. Effect of grapefruit juice on the disposition of nicardipine after administration of intravenous and oral doses [abstract]. Clin Pharmacol Ther 1999; 61: 209.Google Scholar
  90. 90.
    Rashid TJ, Martin U, Clarke H, et al. Factors affecting the absolute bioavailability of nifedipine. Br J Clin Pharmacol 1995; 40: 51–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Sigusch H, Hippius M, Henschel L, et al. Influence of grapefruit juice on the pharmacokinetics of a slow release nifedipine formulation. Pharmazie 1994; 49: 522–4.PubMedGoogle Scholar
  92. 92.
    Fuhr U, Maier-Bruggemann A, Blume H, et al. Grapefruit juice increases oral nimodipine bioavailability. Int J Clin Pharmacol Ther 1998; 36: 126–32.PubMedGoogle Scholar
  93. 93.
    Bailey DG, Arnold JM, Strong HA, et al. Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics. Clin Pharmacol Ther 1993; 54: 589–94.PubMedCrossRefGoogle Scholar
  94. 94.
    Soons PA, Vogels BA, Roosemalen MC, et al. Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans. Clin Pharmacol Ther 1991; 50: 394–403.PubMedCrossRefGoogle Scholar
  95. 95.
    Bailey DG, Munoz C, Arnold JM, et al. Grapefruit juice and naringin interaction with nitrendipine [abstract]. Clin Pharmacol Ther 1992; 51: 156.Google Scholar
  96. 96.
    Hashimoto K, Shirafuji T, Sekino H, et al. Interaction of citrus juices with pranidipine, a new 1,4-dihydropyridine-calcium antagonist, in healthy subjects. Eur J Clin Pharmacol 1998; 54: 753–60.PubMedCrossRefGoogle Scholar
  97. 97.
    Billups SJ, Carter BL. Mibefradil: a new class of calcium-channel antagonists [review]. Ann Pharmacother 1998; 32: 659–71.PubMedCrossRefGoogle Scholar
  98. 98.
    Mullins ME, Horowitz BZ, Linden DH, et al. Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers. JAMA 1998; 280: 157–8.PubMedCrossRefGoogle Scholar
  99. 99.
    Langtry HD, Markham A. Sildenafil: a review of its use in erectile dysfunction [review]. Drugs 1999; 57: 967–89.PubMedCrossRefGoogle Scholar
  100. 100.
    Walker DK, Ackland MJ, James GC, et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 1999; 29: 297–310.PubMedCrossRefGoogle Scholar
  101. 101.
    Webb DJ, Freestone S, Allen MJ, et al. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am JCardiol 1999; 83: 21C–8C.CrossRefGoogle Scholar
  102. 102.
    Cheitlin MD, Hutter AMJ, Brindis RG, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College Cardiology/American Heart Association [review]. J Am Coll Cardiol 1999; 33: 273–82.PubMedCrossRefGoogle Scholar
  103. 103.
    Nandwani R, Gourlay Y. Possible interaction between sildenafil and HIV combination therapy [letter]. Lancet 1999; 353: 840.PubMedCrossRefGoogle Scholar
  104. 104.
    Hall MC, Ahmad S. Interaction between sildenafil and HIV-1 combination therapy [letter]. Lancet 1999; 353: 2071–2.PubMedCrossRefGoogle Scholar
  105. 105.
    Olkkola KT, Aranko K, Luurila H, et al. Apotentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther 1993; 53: 298–305.PubMedCrossRefGoogle Scholar
  106. 106.
    Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 56: 601–7.PubMedCrossRefGoogle Scholar
  107. 107.
    von Moltke LL, Greenblatt DJ, Harmatz JS, et al. Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Pharmacol Exp Ther 1996; 276: 370–9.Google Scholar
  108. 108.
    Yasui N, Otani K, Kaneko S, et al. A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in alprazolam metabolism. Clin Pharmacol Ther 1996; 59: 514–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Ozdemir M, Aktan Y, Boydag BS, et al. Interaction between grapefruit juice and diazepam in humans. Eur J Drug Metab Pharmacokinet 1998; 23: 55–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Aranko K, Luurila H, Backman JT, et al. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone. Br J Clin Pharmacol 1994; 38: 363–7.PubMedCrossRefGoogle Scholar
  111. 111.
    Lilja JJ, Kivisto KT, Backman JT, et al. Grapefruit juice substantially increases plasma concentrations of buspirone. Clin Pharmacol Ther 1998; 64: 655–60.PubMedCrossRefGoogle Scholar
  112. 112.
    Paine MF, Shen DD, Kunze KL, et al. First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther 1996; 60: 14–24.PubMedCrossRefGoogle Scholar
  113. 113.
    Backman JT, Kivisto KT, Olkkola KT, et al. 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 1998; 54: 53–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55: 481–5.PubMedCrossRefGoogle Scholar
  115. 115.
    Yeates RA, Laufen H, Zimmermann T. Interaction between midazolam and clarithromycin: comparison with azithromycin. Int J Clin Pharmacol Ther 1996; 34: 400–5.PubMedGoogle Scholar
  116. 116.
    Backman JT, Olkkola KT, Aranko K, et al. Dose of midazolam should be reduced during diltiazem and verapamil treatments. Br J Clin Pharmacol 1994; 37: 221–5.PubMedCrossRefGoogle Scholar
  117. 117.
    Kupferschmidt HH, Ha HR, Ziegler WH, et al. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther 1995; 58: 20–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Luurila H, Olkkola KT, Neuvonen PJ. Lack of interaction of erythromycin with temazepam. Ther Drug Monit 1994; 16: 548–51.PubMedCrossRefGoogle Scholar
  119. 119.
    Luurila H, Olkkola KT, Neuvonen PJ. Interaction between erythromycin and nitrazepam in healthy volunteers. Pharmacol Toxicol 1995; 76: 255–8.PubMedCrossRefGoogle Scholar
  120. 120.
    Greene DS, Salazar DE, Dockens RC, et al. Coadministration of nefazodone and benzodiazepines: IV. A pharmacokinetic interaction study with lorazepam. J Clin Psychopharmacol 1995; 15: 409–16.PubMedCrossRefGoogle Scholar
  121. 121.
    Olkkola KT, Ahonen J, Neuvonen PJ. The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 1996; 82: 511–6.PubMedGoogle Scholar
  122. 122.
    Baciewicz AM. Carbamazepine drug interactions [review]. Ther Drug Monit 1986; 8: 305–17.PubMedCrossRefGoogle Scholar
  123. 123.
    Lai AA, Levy RH, Cutler RE. Time-course of interaction between carbamazepine and clonazepam in normal man. Clin Pharmacol Ther 1978; 24: 316–23.PubMedGoogle Scholar
  124. 124.
    Loiseau P, Guyot M, Pautrizel B, et al. Carbamazepine poisoning caused by carbamazepine-erythromycin interaction [letter]. Presse Med 1985; 14: 162.PubMedGoogle Scholar
  125. 125.
    Berrettini WH. A case of erythromycin-induced carbamazepine toxicity [case report]. J Clin Psychiatry 1986; 47: 147.PubMedGoogle Scholar
  126. 126.
    Brodie MJ, MacPhee GJ. Carbamazepine neurotoxicity precipitated by diltiazem. BMJ (Clin Res Ed) 1986; 292: 1170–1.CrossRefGoogle Scholar
  127. 127.
    Maoz E, Grossman E, Thaler M, et al. Carbamazepine neurotoxic reaction after administration of diltiazem. Arch Intern Med 1992; 152: 2503–4.PubMedCrossRefGoogle Scholar
  128. 128.
    Beattie B, Biller J, Mehlhaus B, et al. Verapamil-induced carbamazepine neurotoxicity: a report of two cases. Eur Neurol 1988; 28: 104–5.PubMedCrossRefGoogle Scholar
  129. 129.
    Pearson HJ. Interaction of fluoxetine with carbamazepine [letter]. J Clin Psychiatry 1990; 51: 126.PubMedGoogle Scholar
  130. 130.
    Fritze J, Unsorg B, Lanczik M. Interaction between carbamazepine and fluvoxamine. Acta Psychiatr Scand 1991; 84: 583–4.PubMedCrossRefGoogle Scholar
  131. 131.
    Albani F, Riva R, Baruzzi A. Clarithromycin-carbamazepine interaction: a case report. Epilepsia 1993; 34: 161–2.PubMedCrossRefGoogle Scholar
  132. 132.
    Ashton AK, Wolin RE. Nefazodone-induced carbamazepine toxicity [letter]. Am J Psychiatry 1996; 153: 733.PubMedGoogle Scholar
  133. 133.
    Grimsley SR, Jann MW, Carter JG, et al. Increased carbamazepine plasma concentrations after fluoxetine coadministration. Clin Pharmacol Ther 1991; 50: 10–5.PubMedCrossRefGoogle Scholar
  134. 134.
    Barzaghi N, Gatti G, Crema F, et al. Inhibition by erythromycin of the conversion of carbamazepine to its active 10, 11-epoxide metabolite. Br J Clin Pharmacol 1987; 24: 836–8.PubMedCrossRefGoogle Scholar
  135. 135.
    Miles MV, Tennison MB. Erythromycin effects on multiple-dose carbamazepine kinetics. Ther Drug Monit 1989; 11: 47–52.PubMedCrossRefGoogle Scholar
  136. 136.
    Preskorn SH, Alderman J, Greenblatt DJ, et al. Sertraline does not inhibit cytochrome P450 3A-mediated drug metabolism in vivo. Psychopharmacol Bull 1997; 33: 659–65.PubMedGoogle Scholar
  137. 137.
    Silberstein SD. The pharmacology of ergotamine and dihydroergotamine [review]. Headache 1997; 37 Suppl. 1: S15–25.Google Scholar
  138. 138.
    Sanders SW, Haering N, Mosberg H, et al. Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing. Eur J Clin Pharmacol 1986; 30: 331–4.PubMedCrossRefGoogle Scholar
  139. 139.
    Tfelt-Hansen P, Paalzow L, Ibraheem JJ. Bioavailability of sub-lingual ergotamine. Br J Clin Pharmacol 1982; 13: 239–40.PubMedCrossRefGoogle Scholar
  140. 140.
    Ekbom K, Paalzow L, Waldenlind E. Low biological availability of ergotamine tartrate after oral dosing in cluster headache. Cephalalgia 1981; 1: 203–7.PubMedCrossRefGoogle Scholar
  141. 141.
    Horowitz RS, Dart RC, Gomez HE. Clinical ergotism with lingual ischemia induced by clarithromycin-ergotamine interaction. Arch Intern Med 1996; 156: 456–8.PubMedCrossRefGoogle Scholar
  142. 142.
    Caballero-Granado FJ, Viciana P, Cordero E, et al. Ergotism related to concurrent administration of ergotamine tartrate and ritonavir in an AIDS patient [letter]. Antimicrob Agents Chemother 1997; 41: 1207.PubMedGoogle Scholar
  143. 143.
    Liaudet L, Buclin T, Jaccard C, et al. Drug points: severe ergotism associated with interaction between ritonavir and ergotamine [case report]. BMJ (Clin Res Ed) 1999; (7186): 7711.Google Scholar
  144. 144.
    Hayton AC. Precipitation of acute ergotism by triacetyloleandomycin [case report]. N Z Med J 1969; 69: 42.PubMedGoogle Scholar
  145. 145.
    Gomez DY, Wacher VJ, Tomlanovich SJ, et al. The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Pharmacol Ther 1995; 58: 15–9.PubMedCrossRefGoogle Scholar
  146. 146.
    First MR, Schroeder TJ, Michael A, et al. Cyclosporine-ketoconazole interaction: long-term follow-up and preliminary results of a randomized trial. Transplantation 1993; 55: 1000–4.PubMedCrossRefGoogle Scholar
  147. 147.
    Keogh A, Spratt P, McCosker C, et al. Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl J Med 1995; 333: 628–33.PubMedCrossRefGoogle Scholar
  148. 148.
    Ducharme MP, Warbasse LH, Edwards DJ. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther 1995; 57: 485–91.PubMedCrossRefGoogle Scholar
  149. 149.
    Hollander AA, van Rooij J, Lentjes GW, et al. The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin Pharmacol Ther 1995; 57: 318–24.PubMedCrossRefGoogle Scholar
  150. 150.
    Min DI, Ku YM, Perry PJ, et al. Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients. Transplantation 1996; 62: 123–5.PubMedCrossRefGoogle Scholar
  151. 151.
    Ioannides-Demos LL, Christophidis N, Ryan P, et al. Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases. J Rheumatol 1997; 24: 49–54.PubMedGoogle Scholar
  152. 152.
    Brunner LJ, Munar MY, Vallian J, et al. Interaction between cyclosporine and grapefruit juice requires long-term ingestion in stable renal transplant recipients. Pharmacotherapy 1998; 18: 23–9.PubMedGoogle Scholar
  153. 153.
    Barry M, Gibbons S, Back D, et al. Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations [review]. Clin Pharmacokinet 1997; 32: 194–209.PubMedCrossRefGoogle Scholar
  154. 154.
    Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 1997; 44: 190–4.PubMedCrossRefGoogle Scholar
  155. 155.
    Gutmann H, Fricker G, Drewe J, et al. Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol Pharmacol 1999; 56: 383–9.PubMedGoogle Scholar
  156. 156.
    Merry C, Barry MG, Mulcahy F, et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-in-fected patients. AIDS 1997; 11: F29–F33.PubMedCrossRefGoogle Scholar
  157. 157.
    Kupferschmidt HH, Fattinger KE, Ha HR, et al. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br J Clin Pharmacol 1998; 45: 355–9.PubMedCrossRefGoogle Scholar
  158. 158.
    Blychert E, Edgar B, Elmfeldt D, et al. Plasma concentration-effect relationships for felodipine: a meta analysis. Clin Pharmacol Ther 1992; 52: 80–9.PubMedCrossRefGoogle Scholar
  159. 159.
    Furberg CD, Psaty BM. Corrections to the nifedipine meta-analysis [letter]. Circulation 1996; 93: 1475–6.PubMedGoogle Scholar
  160. 160.
    Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326–31.PubMedCrossRefGoogle Scholar
  161. 161.
    Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998; 63: 397–402.PubMedCrossRefGoogle Scholar
  162. 162.
    Rogers JD, Vega JM, Zhao J, et al. Grapefruit juice (GFJ) has a small effect on lovastatin plasma HMG-CoA reductase inhibitor (HMGRI) profiles [abstract]. Clin Pharmacol Ther 1999; 65: 149.CrossRefGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • George K. Dresser
    • 1
    • 2
  • J. David Spence
    • 1
    • 2
    • 3
  • David G. Bailey
    • 1
    • 2
    Email author
  1. 1.Department of MedicineLondon Health Sciences Centre and The University of Western OntarioLondonCanada
  2. 2.Department of Pharmacology & ToxicologyLondon Health Sciences Centre and The University of Western OntarioLondonCanada
  3. 3.Department of NeurologyLondon Health Sciences Centre and The University of Western OntarioLondonCanada

Personalised recommendations