Current Fungal Infection Reports

, Volume 3, Issue 2, pp 111–116 | Cite as

Pharmacogenomics of systemic antifungal agents

  • Melissa D. JohnsonEmail author


The genomic era offers a multitude of new technologies that may make the promise of personalized medicine a reality for patients in this century. Numerous new antifungal agents have been developed over the past two decades, but use of these agents requires optimization of pharmacokinetics and dosing to achieve efficacy and minimize toxicity. This article reviews the potential application of pharmacogenomics to the use of antifungal agents, highlighting genetic variation that may affect absorption, distribution, metabolism, and elimination of these compounds.


Itraconazole Ketoconazole Voriconazole Azole Antifungal Agent 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Huang SM, Goodsaid F, Rahman A, et al.: Application of pharmacogenomics in clinical pharmacology. Toxicol Mech Method 2006, 16:89–99.CrossRefGoogle Scholar
  2. 2.
    US Food and Drug Administration: Genomics at FDA. Available at Accessed April 5, 2009.
  3. 3.
    Meletiadis J, Chanock S, Walsh TJ: Human pharmacogenomic variations and their implications for antifungal efficacy. Clin Microbiol Rev 2006, 19:763–787.PubMedCrossRefGoogle Scholar
  4. 4.
    Meletiadis J, Chanock S, Walsh TJ: Defining targets for investigating the pharmacogenomics of adverse drug reactions to antifungal agents. Pharmacogenomics 2008, 9:561–584.PubMedCrossRefGoogle Scholar
  5. 5.
    Dodds Ashley ES, Lewis R, Lewis JS, et al.: Pharmacology of systemic antifungal agents. Clin Infect Dis 2006, 43:S28–S39.CrossRefGoogle Scholar
  6. 6.
    Krishna G, Moton A, Ma L, et al.: Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother 2009, 53:958–966.PubMedCrossRefGoogle Scholar
  7. 7.
    Blum RA, D’Andrea DT, Florentino BM, et al.: Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern Med 1991, 114:755–757.PubMedGoogle Scholar
  8. 8.
    Courtney R, Radwanski E, Lim J, Laughlin M: Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men. Antimicrob Agents Chemother 2004, 48:804–808.PubMedCrossRefGoogle Scholar
  9. 9.
    Carlson JA, Mann HJ, Canafax DM: Effect of pH on disintegration and dissolution of ketoconazole tablets. Am J Hosp Pharm 1983, 40:1334–1336.PubMedGoogle Scholar
  10. 10.
    Van Der Meer JW, Keuning JJ, Scheijgrond HW, et al.: The influence of gastric acidity on the bio-availability of ketoconazole. J Antimicrob Chemother 1980, 6:552–554.CrossRefGoogle Scholar
  11. 11.
    Drew RH, Perfect JR, Gallis HA: Use of fluconazole in a patient with documented malabsorption of ketoconazole. Clin Pharm 1988, 7:622–623.PubMedGoogle Scholar
  12. 12.
    Courtney R, Wexler D, Radwanski E, et al.: Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol 2004, 57:218–222.PubMedCrossRefGoogle Scholar
  13. 13.
    Williams MP, Blanshard C, Millson C, et al.: A placebocontrolled study to assess the effects of 7-day dosing with 10, 20 and 40 mg rabeprazole on 24-h intragastric acidity and plasma gastrin in healthy male subjects. Aliment Pharmacol Ther 2000, 14:691–699.PubMedCrossRefGoogle Scholar
  14. 14.
    Welage LS, Carver PL, Revankar S, et al.: Alterations in gastric acidity in patients infected with human immunodeficiency virus. Clin Infect Dis 1995, 21:1431–1438.PubMedGoogle Scholar
  15. 15.
    Hurwitz A, Ruhl CE, Kimler BF, et al.: Gastric function in the elderly: effects on absorption of ketoconazole. J Clin Pharmacol 2003, 43:996–1002.PubMedCrossRefGoogle Scholar
  16. 16.
    Wang EJ, Lew K, Casciano CN, et al.: Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother 2002, 46:160–165.PubMedCrossRefGoogle Scholar
  17. 17.
    Stein WD: Kinetics of the multidrug transporter (P-glycoprotein) and its reversal. Physiol Rev 1997, 77:545–590.PubMedGoogle Scholar
  18. 18.
    Dresser MJ: The MDR1 C3435T polymorphism: effects on P-glycoprotein expression/function and clinical significance. AAPS PharmSci 2001, 3:3.PubMedCrossRefGoogle Scholar
  19. 19.
    Courtney R, Sansone A, Devlin D, et al.: P-glycoprotein expression and genotype: exploratory analysis of posaconazole in healthy volunteers [abstract A-40]. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; October 30–November 2, 2004.Google Scholar
  20. 20.
    Weiss J, Ten Hoevel MM, Burhenne J, et al.: CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol 2009, 49:196–204.PubMedCrossRefGoogle Scholar
  21. 21.
    Cordon-Cardo C, O’Brien JP, Casals D, et al.: Multidrugresistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U SA 1989, 86:695–698.CrossRefGoogle Scholar
  22. 22.
    Miyama T, Takanaga H, Matsuo H, et al.: P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier. Antimicrob Agents Chemother 1998, 42:1738–1744.PubMedGoogle Scholar
  23. 23.
    Evans WE, McLeod HL: Pharmacogenomics-drug disposition, drug targets, and side effects. N Engl J Med 2003, 348:538–549.PubMedCrossRefGoogle Scholar
  24. 24.
    Balani SK, Xu X, Arison BH, et al.: Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Drug Metab Dispos 2000, 28:1274–1278.PubMedGoogle Scholar
  25. 25.
    Joseph JM, Jain R, Danziger LH: Micafungin: a new echinocandin antifungal. Pharmacotherapy 2007, 27:53–67.PubMedCrossRefGoogle Scholar
  26. 26.
    Hebert MF, Smith HE, Marbury TC, et al.: Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J Clin Pharmacol 2005, 45:1145–1152.PubMedCrossRefGoogle Scholar
  27. 27.
    Damle BD, Dowell JA, Walsky RL, et al.: In vitro and in vivo studies to characterize the clearance mechanism and potential cytochrome P450 interactions of anidulafungin. Antimicrob Agents Chemother 2009, 53:1149–1156.PubMedCrossRefGoogle Scholar
  28. 28.
    Brammer KW, Farrow PR, Faulkner JK: Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 1990, 12(Suppl 3):S318–S326.PubMedGoogle Scholar
  29. 29.
    Huang YC, Colaizzi JL, Bierman RH, et al.: Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers. Antimicrob Agents Chemother 1986, 30:206–210.PubMedGoogle Scholar
  30. 30.
    Rodriguez RJ, Acosta D Jr: Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases. Drug Metab Dispos 1997, 25:772–777.PubMedGoogle Scholar
  31. 31.
    Prescribing information: Sporanox (Itraconazole) [package insert]. Ortho-McNeil-Janssen Pharmaceuticals, Inc.; Raritan, NJ: 2001.Google Scholar
  32. 32.
    Yanni SB, Annaert PP, Augustijns P, et al.: Role of flavincontaining monooxygenase in oxidative metabolism of voriconazole by human liver microsomes. Drug Metab Dispos 2008, 36:1119–1125.PubMedCrossRefGoogle Scholar
  33. 33.
    Krieter P, Flannery B, Musick T, et al.: Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agents Chemother 2004, 48:3543–3551.PubMedCrossRefGoogle Scholar
  34. 34.
    Bozina N, Granic P, Lalic Z, et al.: Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. Croat Med J 2003, 44:425–428.PubMedGoogle Scholar
  35. 35.
    Ikeda Y, Umemura K, Kondo K, et al.: Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status. Clin Pharmacol Ther 2004, 75:587–588.PubMedCrossRefGoogle Scholar
  36. 36.
    Wang G, Lei HP, Li Z, et al.: The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers. Eur J Clin Pharmacol 2009, 65:281–285.PubMedCrossRefGoogle Scholar
  37. 37.
    Geist MJ, Egerer G, Burhenne J, Mikus G: Safety of voriconazole in a patient with CYP2C9*2/CYP2C9*2 genotype. Antimicrob Agents Chemother 2006, 50:3227–3228.PubMedCrossRefGoogle Scholar
  38. 38.
    Cashman JR: The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and development. Drug Discov Today 2004, 9:574–581.PubMedCrossRefGoogle Scholar
  39. 39.
    Ghosal A, Hapangama N, Yuan Y, et al.: Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil). Drug Metab Dispos 2004, 32:267–271.PubMedCrossRefGoogle Scholar
  40. 40.
    Sandhu P, Lee W, Xu X, et al.: Hepatic uptake of the novel echinocandin caspofungin. Drug Metab Dispos 2005, 33:676–682.PubMedCrossRefGoogle Scholar
  41. 41.
    Arredondo G, Martinez-Jorda R, Calvo R, et al.: Protein binding of itraconazole and fluconazole in patients with chronic renal failure. Int J Clin Pharmacol Ther 1994, 32:361–364.PubMedGoogle Scholar
  42. 42.
    Arredondo G, Suarez E, Calvo R, et al.: Serum protein binding of itraconazole and fluconazole in patients with diabetes mellitus. J Antimicrob Chemother 1999, 43:305–307.PubMedCrossRefGoogle Scholar
  43. 43.
    Mouton JW, van Peer A, de Beule K, et al.: Pharmacokinetics of itraconazole and hydroxyitraconazole in healthy subjects after single and multiple doses of a novel formulation. Antimicrob Agents Chemother 2006, 50:4096–4102.PubMedCrossRefGoogle Scholar
  44. 44.
    Roffey SJ, Cole S, Comby P, et al.: The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos 2003, 31:731–741.PubMedCrossRefGoogle Scholar
  45. 45.
    Greer ND: Posaconazole (Noxafil): a new triazole antifungal agent. Proc Bayl Univ Med Cent 2007, 20:188–196.PubMedGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  1. 1.Department of Clinical ResearchCampbell University School of PharmacyMorrisvilleUSA
  2. 2.Department of Medicine, Division of Infectious Diseases & International HealthDuke University Medical CenterDurhamUSA

Personalised recommendations