Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Bone Marrow Transplantation volume 47, pages 881–894 (2012)Cite this article

Abstract

Treatment or prophylaxis of invasive fungal infection in recipients of haemopoietic SCT (HSCT) may require management of coexistent malnutrition, organ dysfunction and GVHD, all of which create added potential for inter- and intra-patient variations in drug metabolism as well as drug interactions. Polymorphism is common in genes encoding pathway components of antifungal drug metabolism such as enzymes (cytochrome P450 (CYP450), glutathione S-transferase, N-acetyltransferase and uridine 5′-diphospho-glucuronosyltransferase), uptake transporters (organic cationic transporter, novel organic cationic transporter, organic anion transporter protein (OATP), organic anion transport (OAT), and peptide tranporter) and efflux transporters (breast cancer resistance protein, bile sale export pump (BSEP), multidrug and toxin extrusion type transporter, multidrug resistance protein (MRP), OAT, permeability glycoprotein (P-gp), and urate transporter). Specific polymorphisms may be generalised throughout a population or largely confined to ethnic groups. CYP450 enzymes, especially 2C9 and 2C19, exhibit extensive polymorphism and are central to the metabolism of azole antifungals and their interactions with other drugs including calcineurin inhibitors, cytotoxics and benzodiazepines. Polymorphism may ultimately affect drug efficacy: CYP2C19 variation leads to a fivefold variation in voriconazole levels between individuals. Anticipated routine provision of pharmacogenomic data in the future for new drugs, together with accumulating knowledge about established agents, challenge physicians to assimilate and apply that information to drug prescribing. Increasing availability of pharmacogenomic data may strengthen demand for rapid turn-around therapeutic drug monitoring of antifungal agents in HSCT recipients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Cascorbi I . The promises of personalized medicine. Eur J Clin Pharmacol 2010; 66: 749–754.

    Article  PubMed  Google Scholar 

  2. Andersson T, Flockhart DA, Goldstein DB, Huang SM, Kroetz DL, Milos PM et al. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 2005; 78: 559–581.

    Article  CAS  PubMed  Google Scholar 

  3. Williams MP, Sercombe J, Hamilton MI, Pounder RE . A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther 1998; 12: 1079–1089.

    Article  CAS  PubMed  Google Scholar 

  4. Muscaritoli M, Grieco G, Capria S, Iori AP, Rossi FF . Nutritional and metabolic support in patients undergoing bone marrow transplantation. Am J Clin Nutr 2002; 75: 183–190.

    Article  CAS  PubMed  Google Scholar 

  5. Arredondo G, Calvo R, Marcos F, Martinez-Jorda R, Suarez E . Protein binding of itraconazole and fluconazole in patients with cancer. Int J Clin Pharmacol Ther 1995; 33: 449–452.

    CAS  PubMed  Google Scholar 

  6. Madison J, Galliano M, Watkins S, Minchiotti L, Porta F, Rossi A et al. Genetic variants of human serum albumin in Italy: point mutants and a carboxyl-terminal variant. Proc Natl Acad Sci USA 1994; 91: 6476–6480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Franco MHLP, Brennan SO, Chua EKM, Kragh-Hansen U, Callegari-Jacques SM, Bezerra MZPJ et al. Albumin genetic variability in South America: population distribution and molecular studies. Am J Hum Biol 1999; 11: 359–366.

    Article  PubMed  Google Scholar 

  8. Kragh-Hansen U, Brennan SO, Galliano M, Sugita O . Binding of warfarin, salicylate, and diazepam to genetic variants of human serum albumin with known mutations. Mol Pharmacol 1990; 37: 238–242.

    CAS  PubMed  Google Scholar 

  9. Chowbay B, Zhou S, Lee EJ . An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore. Drug Metab Rev 2005; 37: 327–378.

    Article  CAS  PubMed  Google Scholar 

  10. Cropp CD, Yee SW, Giacomini KM . Genetic variation in drug transporters in ethnic populations. Clin Pharmacol Ther 2008; 84: 412–416.

    Article  CAS  PubMed  Google Scholar 

  11. Yasuda SU, Zhang L, Huang SM . The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies. Clin Pharmacol Ther 2008; 84: 417–423.

    Article  CAS  PubMed  Google Scholar 

  12. Guengerich FP . Cytochrome p450 and chemical toxicology. Chem Res Toxicol 2008; 21: 70–83.

    Article  CAS  PubMed  Google Scholar 

  13. Bruggemann RJM, Alffenaar JWC, Blijlevens NMA, Billaud EM, Kosterink JGW, Verweij PE et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 2009; 48: 1441–1458.

    Article  PubMed  CAS  Google Scholar 

  14. Nivoix Y, Leveque D, Herbrecht R, Koffel JC, Beretz L, Ubeaud-Sequier G . The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet 2008; 47: 779–792.

    Article  CAS  PubMed  Google Scholar 

  15. Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP et al. Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos 2001; 29: 268–273.

    CAS  PubMed  Google Scholar 

  16. Wacher VJ, Wu CY, Benet LZ . Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13: 129–134.

    Article  CAS  PubMed  Google Scholar 

  17. Desta Z, Zhao X, Shin JG, Flockhart DA . Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41: 913–958.

    Article  CAS  PubMed  Google Scholar 

  18. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006; 79: 103–113.

    Article  CAS  PubMed  Google Scholar 

  19. Goldstein JA . Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 2001; 52: 349–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xie HG, Prasad HC, Kim RB, Stein CM . CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev 2002; 54: 1257–1270.

    Article  CAS  PubMed  Google Scholar 

  21. Lamba JK, Lin YS, Schuetz EG, Thummel KE . Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002; 54: 1271–1294.

    Article  CAS  PubMed  Google Scholar 

  22. King BP, Leathart JB, Mutch E, Williams FM, Daly AK . CYP3A5 phenotype-genotype correlations in a British population. Br J Clin Pharmacol 2003; 55: 625–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stubbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR . Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996; 6: 429–439.

    Article  CAS  PubMed  Google Scholar 

  24. Pemble S, Schroeder KR, Spencer SR, Meyer DJ, Hallier E, Bolt HM et al. Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 1994; 300 (Part 1): 271–276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Daly AK . Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam Clin Pharmacol 2003; 17: 27–41.

    Article  CAS  PubMed  Google Scholar 

  26. Guillemette C, Ritter JK, Auyeung DJ, Kessler FK, Housman DE . Structural heterogeneity at the UDP-glucuronosyltransferase 1 locus: functional consequences of three novel missense mutations in the human UGT1A7 gene. Pharmacogenetics 2000; 10: 629–644.

    Article  CAS  PubMed  Google Scholar 

  27. Seidegard J, Vorachek WR, Pero RW, Pearson WR . Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci USA 1988; 85: 7293–7297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dodds Ashley ES, Lewis R, Lewis JS, Martin C, Andes D . Pharmacology of systemic antifungal agents. Clin Infect Dis 2006; 43: S28–S39.

    Article  CAS  Google Scholar 

  29. Herbrecht R, Natarajan-Ame S, Nivoix Y, Letscher-Bru V . The lipid formulations of amphotericin B. Expert Opin Pharmacother 2003; 4: 1277–1287.

    Article  CAS  PubMed  Google Scholar 

  30. Brajtburg J, Elberg S, Bolard J, Kobayashi GS, Levy RA, Ostlund Jr RE et al. Interaction of plasma proteins and lipoproteins with amphotericin B. J Infect Dis 1984; 149: 986–997.

    Article  CAS  PubMed  Google Scholar 

  31. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ . Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate. Antimicrob Agents Chemother 2002; 46: 834–840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bartell A, Phatak A, Horn K, Postelnick MJ . Drug interactions involving antifungal drugs: time course and clinical significance. Curr Fungal Infect Rep 2010; 4: 103–110.

    Article  Google Scholar 

  33. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ . Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother 2002; 46: 828–833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Adler-Moore JP, Proffitt RT . AmBisome: liposomal formulation, structure, mechanism of action and pre-clinical experience. J Antimicrob Chemother 2002; 49: 21–30.

    Article  CAS  PubMed  Google Scholar 

  35. Brockmeyer NH, Gambichler T, Bader A, Kreuter A, Kurowski M, Sander P et al. Impact of amphotericin B on the cytochrome P450 system in HIV-infected patients. Eur J Med Res 2004; 9: 51–54.

    CAS  PubMed  Google Scholar 

  36. Ishizaki J, Ito S, Jin M, Shimada T, Ishigaki T, Harasawa Y et al. Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B. Biopharm Drug Dispos 2008; 29: 195–203.

    Article  CAS  PubMed  Google Scholar 

  37. Georgopapadakou NH . Antifungals: mechanism of action and resistance, established and novel drugs. Curr Opin Microbiol 1998; 1: 547–557.

    Article  CAS  PubMed  Google Scholar 

  38. Egger SS, Meier S, Leu C, Christen S, Gratwohl A, Krahenbuhl S et al. Drug interactions and adverse events associated with antimycotic drugs used for invasive aspergillosis in hematopoietic SCT. Bone Marrow Transplant 2010; 45: 1197–1203.

    Article  CAS  PubMed  Google Scholar 

  39. Humphrey MJ, Jevons S, Tarbit MH . Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans. Antimicrob Agents Chemother 1985; 28: 648–653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Blum RA, D’Andrea DT, Florentino BM, Wilton JH, Hilligoss DM, Gardner MJ et al. Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern Med 1991; 114: 755–757.

    Article  CAS  PubMed  Google Scholar 

  41. Brammer KW, Farrow PR, Faulkner JK . Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis 1990; 12: 318–327.

    Article  Google Scholar 

  42. Thaler F, Bernard B, Tod M, Jedynak CP, Petitjean O, Derome P et al. Fluconazole penetration in cerebral parenchyma in humans at steady state. Antimicrob Agents Chemother 1995; 39: 1154–1156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Brammer KW, Coakley AJ, Jezequel SG, Tarbit MH . The disposition and metabolism of [14C]fluconazole in humans. Drug Metab Dispos 1991; 19: 764–767.

    CAS  PubMed  Google Scholar 

  44. Venkatakrishnan K, von Moltke LL, Greenblatt DJ . Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 2000; 38: 111–180.

    Article  CAS  PubMed  Google Scholar 

  45. Niwa T, Shiraga T, Takagi A . Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull 2005; 28: 1805–1808.

    Article  CAS  PubMed  Google Scholar 

  46. Kunze KL, Wienkers LC, Thummel KE, Trager WF . Warfarin-fluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies. Drug Metab Dispos 1996; 24: 414–421.

    CAS  PubMed  Google Scholar 

  47. Marr KA, Leisenring W, Crippa F, Slattery JT, Corey L, Boeckh M et al. Cyclophosphamide metabolism is affected by azole antifungals. Blood 2004; 103: 1557–1559.

    Article  CAS  PubMed  Google Scholar 

  48. Upton A, McCune JS, Kirby KA, Leisenring W, McDonald G, Batchelder A et al. Fluconazole coadministration concurrent with cyclophosphamide conditioning may reduce regimen-related toxicity postmyeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant 2007; 13: 760–764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bourcier K, Hyland R, Kempshall S, Jones R, Maximilien J, Irvine N et al. Investigation into UDP-glucuronosyltransferase (UGT) enzyme kinetics of imidazole- and triazole-containing antifungal drugs in human liver microsomes and recombinant UGT enzymes. Drug Metab Dispos 2010; 38: 923–929.

    Article  CAS  PubMed  Google Scholar 

  50. Uchaipichat V, Winner LK, Mackenzie PI, Elliot DJ, Williams JA, Miners JO . Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: the effect of fluconazole on zidovudine glucuronidation. Br J Clin Pharmacol 2006; 61: 427–439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Raungrut P, Uchaipichat V, Elliot DJ, Janchawee B, Somogyi AA, Miners JO . In vitro-in vivo extrapolation predicts drug-drug interactions arising from inhibition of codeine glucuronidation by dextropropoxyphene, fluconazole, ketoconazole, and methadone in humans. J Pharmacol Exp Ther 2010; 334: 609–618.

    Article  CAS  PubMed  Google Scholar 

  52. van Peer A, Woestenborghs R, Heykants J, Gasparini R, Gauwenbergh G . The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol 1989; 36: 423–426.

    Article  CAS  PubMed  Google Scholar 

  53. Lange D, Pavao JH, Wu J, Klausner M . Effect of a cola beverage on the bioavailability of itraconazole in the presence of H2 blockers. J Clin Pharmacol 1997; 37: 535–540.

    Article  CAS  PubMed  Google Scholar 

  54. Bae SK, Park SJ, Shim EJ, Mun JH, Kim EY, Shin JG et al. Increased oral bioavailability of itraconazole and its active metabolite, 7-hydroxyitraconazole, when coadministered with a vitamin C beverage in healthy participants. J Clin Pharmacol 2011; 51: 444–451.

    Article  CAS  PubMed  Google Scholar 

  55. Barone JA, Moskovitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman RH et al. Enhanced bioavailability of itraconazole in hydroxypropyl-beta-cyclodextrin solution versus capsules in healthy volunteers. Antimicrob Agents Chemother 1998; 42: 1862–1865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Glasmacher A, Hahn C, Molitor E, Marklein G, Sauerbruch T, Schmidt-Wolf IG . Itraconazole trough concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-beta-cyclodextrin oral solution or coated-pellet capsules. Mycoses 1999; 42: 591–600.

    Article  CAS  PubMed  Google Scholar 

  57. Poirier JM, Cheymol G . Optimisation of itraconazole therapy using target drug concentrations. Clin Pharmacokinet 1998; 35: 461–473.

    Article  CAS  PubMed  Google Scholar 

  58. Colburn DE, Giles FJ, Oladovich D, Smith JA . In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology 2004; 9: 217–221.

    Article  CAS  PubMed  Google Scholar 

  59. Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE . Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab Dispos 2004; 32: 1121–1131.

    Article  CAS  PubMed  Google Scholar 

  60. Templeton IE, Thummel KE, Kharasch ED, Kunze KL, Hoffer C, Nelson WL et al. Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo. Clin Pharmacol Ther 2008; 83: 77–85.

    Article  CAS  PubMed  Google Scholar 

  61. Johnson LB, Kauffman CA . Voriconazole: a new triazole antifungal agent. Clin Infect Dis 2003; 36: 630–637.

    Article  CAS  PubMed  Google Scholar 

  62. Lazarus HM, Blumer JL, Yanovich S, Schlamm H, Romero A . Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol 2002; 42: 395–402.

    Article  CAS  PubMed  Google Scholar 

  63. Denning DW, Ribaud P, Milpied N, Caillot D, Herbrecht R, Thiel E et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002; 34: 563–571.

    Article  CAS  PubMed  Google Scholar 

  64. Bruggemann RJ, Blijlevens NM, Burger DM, Franke B, Troke PF, Donnelly JP . Pharmacokinetics and safety of 14 days intravenous voriconazole in allogeneic haematopoietic stem cell transplant recipients. J Antimicrob Chemother 2010; 65: 107–113.

    Article  PubMed  CAS  Google Scholar 

  65. Roffey SJ, Cole S, Comby P, Gibson D, Jezequel SG, Nedderman AN et al. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos 2003; 31: 731–741.

    Article  CAS  PubMed  Google Scholar 

  66. Wakiec R, Prasad R, Morschhauser J, Barchiesi F, Borowski E, Milewski S . Voriconazole and multidrug resistance in Candida albicans. Mycoses 2007; 50: 109–115.

    Article  CAS  PubMed  Google Scholar 

  67. Weiss J, Ten Hoevel MM, Burhenne J, Walter-Sack I, Hoffmann MM, Rengelshausen J et al. CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol 2009; 49: 196–204.

    Article  CAS  PubMed  Google Scholar 

  68. Ikeda Y, Umemura K, Kondo K, Sekiguchi K, Miyoshi S, Nakashima M . Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status. Clin Pharmacol Ther 2004; 75: 587–588.

    Article  CAS  PubMed  Google Scholar 

  69. Wang G, Lei HP, Li Z, Tan ZR, Guo D, Fan L 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.

    Article  CAS  PubMed  Google Scholar 

  70. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Liu P, Foster G, La Badie R, Somoza E, Sharma A . Pharmacokinetic interaction between voriconazole and methadone at steady state in patients on methadone therapy. Antimicrob Agents Chemother 2007; 51: 110–118.

    Article  CAS  PubMed  Google Scholar 

  72. Mikus G, Schowel V, Drzewinska M, Rengelshausen J, Ding R, Riedel KD et al. Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther 2006; 80: 126–135.

    Article  CAS  PubMed  Google Scholar 

  73. Hyland R, Jones BC, Smith DA . Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos 2003; 31: 540–547.

    Article  CAS  PubMed  Google Scholar 

  74. Murayama N, Imai N, Nakane T, Shimizu M, Yamazaki H . Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes. Biochem Pharmacol 2007; 73: 2020–2026.

    Article  CAS  PubMed  Google Scholar 

  75. Yanni SB, Annaert PP, Augustijns P, Bridges A, Gao Y, Benjamin Jr DK et al. Role of flavin-containing monooxygenase in oxidative metabolism of voriconazole by human liver microsomes. Drug Metab Dispos 2008; 36: 1119–1125.

    Article  CAS  PubMed  Google Scholar 

  76. Cashman JR, Zhang J . Interindividual differences of human flavin-containing monooxygenase 3: genetic polymorphisms and functional variation. Drug Metab Dispos 2002; 30: 1043–1052.

    Article  CAS  PubMed  Google Scholar 

  77. Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose PG et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50: 1570–1572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O . Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 2008; 46: 201–211.

    Article  CAS  PubMed  Google Scholar 

  79. Miyakis S, van Hal SJ, Ray J, Marriott D . Voriconazole concentrations and outcome of invasive fungal infections. Clin Microbiol Infect 2010; 16: 927–933.

    Article  CAS  PubMed  Google Scholar 

  80. Courtney R, Wexler D, Radwanski E, Lim J, Laughlin M . Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol 2004; 57: 218–222.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Courtney R, Pai S, Laughlin M, Lim J, Batra V . Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother 2003; 47: 2788–2795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Krishna G, Moton A, Ma L, Medlock MM, McLeod J . Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother 2009; 53: 958–966.

    Article  CAS  PubMed  Google Scholar 

  83. Sansone-Parsons A, Krishna G, Calzetta A, Wexler D, Kantesaria B, Rosenberg MA et al. Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers. Antimicrob Agents Chemother 2006; 50: 1881–1883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Courtney R, Wexler D, Statkevich P, Laughlin M . Effect of cimetidine on the pharmacokinetics of posaconazole in healthy volunteers. Intersci Conf Antimicrob Agents Chemother 2002 Abstract A-1838.

  85. Nagappan V, Deresinski S . Letter—Reply to Cornely and Ullmann and to Jain and Pottinger. Clin Infect Dis 2008; 46: 1627–1628.

    Article  Google Scholar 

  86. Courtney R, Sansone-Parsons A, Devlin D, Soni P, Laughlin M, Simon J . P-Glycoprotein (P-gp) expression and genotype: exploratory analysis of posaconazole (POS) in healthy volunteers. Intersci Conf Antimicrob Agents Chemother 2004 Abstract A-40.

  87. Li Y, Theuretzbacher U, Clancy CJ, Nguyen MH, Derendorf H . Pharmacokinetic/pharmacodynamic profile of posaconazole. Clin Pharmacokinet 2010; 49: 379–396.

    Article  CAS  PubMed  Google Scholar 

  88. Kim H, Kumari P, Laughlin M, Hilbert MJ, Indelicato SR, Lim J et al. Use of high-performance liquid chromatographic and microbiological analyses for evaluating the presence or absence of active metabolites of the antifungal posaconazole in human plasma. J Chromatogr A 2003; 987: 243–248.

    Article  CAS  PubMed  Google Scholar 

  89. Krieter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R . Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agents Chemother 2004; 48: 3543–3551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ghosal A, Hapangama N, Yuan Y, Achanfuo-Yeboah J, Iannucci R, Chowdhury S et al. Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil). Drug Metab Dispos 2004; 32: 267–271.

    Article  CAS  PubMed  Google Scholar 

  91. Benoit-Biancamano MO, Adam JP, Bernard O, Court MH, Leblanc MH, Caron P et al. A pharmacogenetics study of the human glucuronosyltransferase UGT1A4. Pharmacogenet Genomics 2009; 19: 945–954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mori A, Maruo Y, Iwai M, Sato H, Takeuchi Y . UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation. Drug Metab Dispos 2005; 33: 672–675.

    Article  CAS  PubMed  Google Scholar 

  93. Krishna G, Sansone-Parsons A, Kantesaria B . Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men. Curr Med Res Opin 2007; 23: 1415–1422.

    Article  CAS  PubMed  Google Scholar 

  94. Denning DW . Echinocandin antifungal drugs. Lancet 2003; 363: 1142–1151.

    Article  CAS  Google Scholar 

  95. Stone JA, Xu X, Winchell GA, Deutsch PJ, Pearson PG, Migoya EM et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob Agents Chemother 2004; 48: 815–823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sandhu P, Lee W, Xu X, Leake BF, Yamazaki M, Stone JA et al. Hepatic uptake of the novel antifungal agent caspofungin. Drug Metab Dispos 2005; 33: 676–682.

    Article  CAS  PubMed  Google Scholar 

  97. Wagner C, Graninger W, Presterl E, Joukhadar C . The echinocandins: comparison of their pharmacokinetics, pharmacodynamics and clinical applications. Pharmacology 2006; 78: 161–177.

    Article  CAS  PubMed  Google Scholar 

  98. Balani SK, Xu X, Arison BH, Silva MV, Gries A, DeLuna FA et al. Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Drug Metab Dispos 2000; 28: 1274–1278.

    CAS  PubMed  Google Scholar 

  99. Stone JA, Migoya EM, Hickey L, Winchell GA, Deutsch PJ, Ghosh K et al. Potential for interactions between caspofungin and nelfinavir or rifampin. Antimicrob Agents Chemother 2004; 48: 4306–4314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Vormfelde SV, Toliat MR, Schirmer M, Meineke I, Nurnberg P, Brockmoller J . The polymorphisms Asn130Asp and Val174Ala in OATP1B1 and the CYP2C9 allele *3 independently affect torsemide pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2008; 83: 815–817.

    Article  CAS  PubMed  Google Scholar 

  101. Chandrasekar PH, Sobel JD . Micafungin: a new echinocandin. Clin Infect Dis 2006; 42: 1171–1178.

    Article  CAS  PubMed  Google Scholar 

  102. Yanni SB, Augustijns PF, Benjamin Jr DK, Brouwer KL, Thakker DR, Annaert PP . In vitro investigation of the hepatobiliary disposition mechanisms of the antifungal agent micafungin in humans and rats. Drug Metab Dispos 2010; 38: 1848–1856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Groll AH, Stergiopoulou T, Roilides E, Walsh TJ . Micafungin: pharmacology, experimental therapeutics and clinical applications. Expert Opin Investig Drugs 2005; 14: 489–509.

    Article  CAS  PubMed  Google Scholar 

  104. Hebert MF, Smith HE, Marbury TC, Swan SK, Smith WB, Townsend RW 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.

    Article  CAS  PubMed  Google Scholar 

  105. Gort L, Coll MJ, Chabas A . Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients. Hum Mutat 1999; 14: 240–248.

    Article  CAS  PubMed  Google Scholar 

  106. Sucher AJ, Chahine EB, Balcer HE . Echinocandins: the newest class of antifungals. Ann Pharmacother 2009; 43: 1647–1657.

    Article  CAS  PubMed  Google Scholar 

  107. Dowell JA, Knebel W, Ludden T, Stogniew M, Krause D, Henkel T . Population pharmacokinetic analysis of anidulafungin, an echinocandin antifungal. J Clin Pharmacol 2004; 44: 590–598.

    Article  CAS  PubMed  Google Scholar 

  108. Inskeep PB, Lin J . Plasma protein binding of anidulafungin is similar to other major echinocandins. 18th Eur Congr Clin Microbiol Infect Dis 2008 Abstract P1048.

  109. Inskeep PB, Walsky RL, Feng B, Campbell S . Lack of anidulafungin interactions with CYP enzymes and transporters in in vivo and in vitro systems. 18th Eur Congr Clin Microbiol Infect Dis 2008 Abstract P1049.

  110. Damle BD, Dowell JA, Walsky RL, Weber GL, Stogniew M, Inskeep PB . 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.

    Article  CAS  PubMed  Google Scholar 

  111. Lewis RE . Antifungal therapeutic drug monitoring. Curr Fungal Infect Rep 2010; 4: 158–167.

    Article  Google Scholar 

  112. Goodwin ML, Drew RH . Antifungal serum concentration monitoring: an update. J Antimicrob Chemother 2008; 61: 17–25.

    Article  CAS  PubMed  Google Scholar 

  113. Hussaini T, Ruping MJ, Farowski F, Vehreschild JJ, Cornely OA . Therapeutic drug monitoring of voriconazole and posaconazole. Pharmacotherapy 2011; 31: 214–225.

    Article  CAS  PubMed  Google Scholar 

  114. Cota JM, Burgess DS . Antifungal dose adjustment in renal and hepatic dysfunction: pharmacokinetic and pharmacodynamic considerations. Curr Fungal Infect Rep 2010; 4: 120–128.

    Article  Google Scholar 

  115. Bruggemann RJ, Touw DJ, Aarnoutse RE, Verweij PE, Burger DM . International interlaboratory proficiency testing program for measurement of azole antifungal plasma concentrations. Antimicrob Agents Chemother 2009; 53: 303–305.

    Article  PubMed  CAS  Google Scholar 

  116. Thompson GR, Rinaldi MG, Pennick G, Dorsey SA, Patterson TF, Lewis JS . Posaconazole therapeutic drug monitoring: a reference laboratory experience. Antimicrob Agents Chemother 2009; 53: 2223–2224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hassan A, Burhenne J, Riedel KD, Weiss J, Mikus G, Haefeli WE et al. Modulators of very low voriconazole concentrations in routine therapeutic drug monitoring. Ther Drug Monit 2011; 33: 86–93.

    Article  CAS  PubMed  Google Scholar 

  118. Bryant AM, Slain D, Cumpston A, Craig M . A post-marketing evaluation of posaconazole plasma concentrations in neutropenic patients with haematological malignancy receiving posaconazole prophylaxis. Int J Antimicrob Agents 2011; 37: 266–269.

    Article  CAS  PubMed  Google Scholar 

  119. Bochud PY, Chien JW, Marr KA, Leisenring W, Upton A, Janer M et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 2008; 359: 1766–1777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Howard SJ, Arendrup MC . Acquired antifungal drug resistance in Aspergillus fumigatus: epidemiology and detection. Med Mycol 2011; 49 (Suppl 1): S90–S95.

    Article  CAS  PubMed  Google Scholar 

  121. Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ . Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect Dis 2009; 9: 789–795.

    Article  CAS  PubMed  Google Scholar 

  122. Snelders E, Van Der Lee HA, Kuijpers J, Rijs AJ, Varga J, Samson RA et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med 2008; 5: e219.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Mardis ER . Next-generation DNA sequencing methods. Annu Rev Genomics Hum Genet 2008; 9: 387–402.

    Article  CAS  PubMed  Google Scholar 

  124. Feldman M, Barnett C . Fasting gastric pH and its relationship to true hypochlorhydria in humans. Dig Dis Sci 1991; 36: 866–869.

    Article  CAS  PubMed  Google Scholar 

  125. Welage LS, Carver PL, Revankar S, Pierson C, Kauffman CA . Alterations in gastric acidity in patients infected with human immunodeficiency virus. Clin Infect Dis 1995; 21: 1431–1438.

    Article  CAS  PubMed  Google Scholar 

  126. Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC et al. Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers. Antimicrob Agents Chemother 1993; 37: 778–784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Jaruratanasirikul S, Sriwiriyajan S . Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol 1998; 54: 159–161.

    Article  CAS  PubMed  Google Scholar 

  128. Hagenbuch B . Drug uptake systems in liver and kidney: a historic perspective. Clin Pharmacol Ther 2010; 87: 39–47.

    Article  CAS  PubMed  Google Scholar 

  129. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007; 117: 1422–1431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kinirons MT, O'Mahony MS . Drug metabolism and ageing. Br J Clin Pharmacol 2004; 57: 540–544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM . The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol 2004; 199: 193–209.

    Article  CAS  PubMed  Google Scholar 

  132. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC . The human intestinal cytochrome P450 “pie”. Drug Metab Dispos 2006; 34: 880–886.

    Article  CAS  PubMed  Google Scholar 

  133. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP . 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: 414–423.

    CAS  PubMed  Google Scholar 

  134. Paine MF, Khalighi M, Fisher JM, Shen DD, Kunze KL, Marsh CL et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther 1997; 283: 1552–1562.

    CAS  PubMed  Google Scholar 

  135. Lin CJ, Tai Y, Huang MT, Tsai YF, Hsu HJ, Tzen KY et al. Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents. J Neurochem 2010; 114: 717–727.

    Article  CAS  PubMed  Google Scholar 

  136. Shikata E, Yamamoto R, Takane H, Shigemasa C, Ikeda T, Otsubo K et al. Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin. J Hum Genet 2007; 52: 117–122.

    Article  CAS  PubMed  Google Scholar 

  137. Terada T, Inui K-I . Gene expression and regulation of drug transporters in the intestine and kidney. Biochem Pharmacol 2007; 73: 440–449.

    Article  CAS  PubMed  Google Scholar 

  138. Ferguson LR, Han DY, Heubner C, Petermann I, Demmers P, McCulloch A et al. Single nucleotide polymorphisms in IL4, OCTN1 and OCTN2 genes in association with inflammatory bowel disease phenotypes in a caucasian population in canterbury, New Zealand. Open Gastroenterol J 2008; 2: 50–56.

    Article  CAS  Google Scholar 

  139. Kalliokoski A, Niemi M . Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 2009; 158: 693–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Iida A, Saito S, Sekine A, Mishima C, Kondo K, Kitamura Y et al. Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic anion-transporting polypeptides, and three NADH:ubiquinone oxidoreductase flavoproteins. J Hum Genet 2001; 46: 668–683.

    Article  CAS  PubMed  Google Scholar 

  141. Zhang L, Zhang Y, Huang SM . Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions. Mol Pharm 2004; 6: 1766–1774.

    Article  CAS  Google Scholar 

  142. Hilgendorf C, Ahlin G, Seithel A, Artursson P, Ungell AL, Karlsson J . Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab Dispos 2007; 35: 1333–1340.

    Article  CAS  PubMed  Google Scholar 

  143. Zamber CP, Lamba JK, Yasuda K, Farnum J, Thummel K, Schuetz JD et al. Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics 2003; 13: 19–28.

    Article  CAS  PubMed  Google Scholar 

  144. Chandra P, Brouwer KLR . The complexities of hepatic drug transport: current knowledge and emerging concepts. Pharm Res 2004; 21: 719–735.

    Article  CAS  PubMed  Google Scholar 

  145. Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL et al. Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics 2010; 20: 45–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Meyer Zu Schwabedissen HE, Verstuyft C, Kroemer HK, Becquemont L, Kim RB . Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol 2010; 298: F997–F1005.

    Article  CAS  PubMed  Google Scholar 

  147. Keitel V, Kartenbeck J, Nies AT, Spring H, Brom M, Keppler D . Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology 2000; 32: 1317–1328.

    Article  CAS  PubMed  Google Scholar 

  148. El-Sheikh AAK, Masereeuw R, Russel FGM . Mechanisms of renal anionic drug transport. Eur J Pharmacol 2008; 585: 245–255.

    Article  CAS  PubMed  Google Scholar 

  149. Xu G, Bhatnagar V, Wen G, Hamilton BA, Eraly SA, Nigam SK . Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)]. Kidney Int 2005; 68: 1491–1499.

    Article  CAS  PubMed  Google Scholar 

  150. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM . P-glycoprotein: from genomics to mechanism. Oncogene 2003; 22: 7468–7485.

    Article  CAS  PubMed  Google Scholar 

  151. Schwab M, Eichelbaum M, Fromm MF . Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol 2003; 43: 285–307.

    Article  CAS  PubMed  Google Scholar 

  152. Shima Y, Teruya K, Ohta H . Association between intronic SNP in urate-anion exchanger gene, SLC22A12, and serum uric acid levels in Japanese. Life Sci 2006; 79: 2234–2237.

    Article  CAS  PubMed  Google Scholar 

  153. Le J, Schiller DS . Aerosolized delivery of antifungal agents. Curr Fungal Infect Rep 2010; 4: 96–102.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Ruhnke M, Yeates RA, Pfaff G, Sarnow E, Hartmann A, Trautmann M . Single-dose pharmacokinetics of fluconazole in patients with liver cirrhosis. J Antimicrob Chemother 1995; 35: 641–647.

    Article  CAS  PubMed  Google Scholar 

  155. Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D . Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 2002; 46: 2546–2553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Shimuzu T, Ochiai H, Asell F, Yokono Y, Kikuchi Y, Nitta M et al. Bioinformatic research on inter-racial difference in drug metabolism II Analysis on relationship between enzyme activities of CYP2D6 and CYP 2C19 and their relevant genotypes. Drug Metab Dispos 2003; 18: 71–78.

    Article  Google Scholar 

  157. Kaneko A, Lum JK, Yaviong L, Takahashi N, Ishizaki T, Bertilsson L et al. High and variable frequencies of CYP2C19 mutations: medical consequences of poor drug metabolism in Vanuatu and other Pacific islands. Pharmacogenetics 1999; 9: 581–590.

    Article  CAS  PubMed  Google Scholar 

  158. Kuti EL, Kuti JL . Pharmacokinetics, antifungal activity and clinical efficacy of anidulafungin in the treatment of fungal infections. Expert Opin Drug Metab Toxicol 2010; 6: 1287–1300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ashley C, Currie A (eds) The Renal Drug Handbook, 2nd edn, Radcliffe Medical Press: Oxford, 2004.

    Google Scholar 

  160. Sakaeda T, Iwaki K, Kakumoto M, Nishikawa M, Niwa T, Jin JS et al. Effect of micafungin on cytochrome P450 3A4 and multidrug resistance protein 1 activities, and its comparison with azole antifungal drugs. J Pharm Pharmacol 2005; 57: 759–764.

    Article  CAS  PubMed  Google Scholar 

  161. Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW . Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother 2002; 46: 160–165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Yasuda K, Lan LB, Sanglard D, Furuya K, Schuetz JD, Schuetz EG . Interaction of cytochrome P450 3A inhibitors with P-glycoprotein. J Pharmacol Exp Ther 2002; 303: 323–332.

    Article  CAS  PubMed  Google Scholar 

  163. Gupta A, Unadkat JD, Mao Q . Interactions of azole antifungal agents with the human breast cancer resistance protein (BCRP). J Pharm Sci 2007; 96: 3226–3235.

    Article  CAS  PubMed  Google Scholar 

  164. Back DJ, Tjia JF . Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes. Br J Clin Pharmacol 1991; 32: 624–626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mihara A, Mori T, Aisa Y, Yamazaki R, Iketani O, Tanigawara Y et al. Greater impact of oral fluconazole on drug interaction with intravenous calcineurin inhibitors as compared with intravenous fluconazole. Eur J Clin Pharmacol 2008; 64: 89–91.

    Article  CAS  PubMed  Google Scholar 

  166. Balayssac D, Authier N, Cayre A, Coudore F . Does inhibition of P-glycoprotein lead to drug-drug interactions? Toxicol Lett 2005; 156: 319–329.

    Article  CAS  PubMed  Google Scholar 

  167. Miyama T, Takanaga H, Matsuo H, Yamano K, Yamamoto K, Iga T et al. P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier. Antimicrob Agents Chemother 1998; 42: 1738–1744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Lennernas H . Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 2003; 42: 1141–1160.

    Article  PubMed  Google Scholar 

  169. Hirano M, Maeda K, Shitara Y, Sugiyama Y . Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos 2006; 34: 1229–1236.

    Article  CAS  PubMed  Google Scholar 

  170. Yoshikado T, Takada T, Yamamoto T, Yamaji H, Ito K, Santa T et al. Itraconazole-induced cholestasis: involvement of the inhibition of bile canalicular phospholipid translocator MDR3/ABCB4. Mol Pharmacol 2011; 79: 241–250.

    Article  CAS  PubMed  Google Scholar 

  171. Buggia I, Zecca M, Alessandrino EP, Locatelli F, Rosti G, Bosi A et al. Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Anticancer Res 1996; 16: 2083–2088.

    CAS  PubMed  Google Scholar 

  172. Varis T, Kivisto KT, Backman JT, Neuvonen PJ . The cytochrome P450 3A4 inhibitor itraconazole markedly increases the plasma concentrations of dexamethasone and enhances its adrenal-suppressant effect. Clin Pharmacol Ther 2000; 68: 487–494.

    Article  CAS  PubMed  Google Scholar 

  173. Olkkola KT, Backman JT, Neuvonen PJ . Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55: 481–485.

    Article  CAS  PubMed  Google Scholar 

  174. Leather H, Boyette RM, Tian L, Wingard JR . Pharmacokinetic evaluation of the drug interaction between intravenous itraconazole and intravenous tacrolimus or intravenous cyclosporin A in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant 2006; 12: 325–334.

    Article  CAS  PubMed  Google Scholar 

  175. Lebrun-Vignes B, Archer VC, Diquet B, Levron JC, Chosidow O, Puech AJ et al. Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects. Br J Clin Pharmacol 2001; 51: 443–450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Gillies J, Hung KA, Fitzsimons E, Soutar R . Severe vincristine toxicity in combination with itraconazole. Clin Lab Haematol 1998; 20: 123–124.

    Article  CAS  PubMed  Google Scholar 

  177. Saad AH, DePestel DD, Carver PL . Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy 2006; 26: 1730–1744.

    Article  CAS  PubMed  Google Scholar 

  178. Takara K, Tanigawara Y, Komada F, Nishiguchi K, Sakaeda T, Okumura K . Cellular pharmacokinetic aspects of reversal effects of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs. Biol Pharm Bull 1999; 22: 1355–1359.

    Article  CAS  PubMed  Google Scholar 

  179. Jeong S, Nguyen PD, Desta Z . Comprehensive in vitro analysis of voriconazole inhibition of eight cytochrome P450 (CYP) enzymes: major effect on CYPs 2B6, 2C9, 2C19, and 3A. Antimicrob Agents Chemother 2009; 53: 541–551.

    Article  CAS  PubMed  Google Scholar 

  180. Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S . Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2009; 44: 371–374.

    Article  CAS  PubMed  Google Scholar 

  181. Groll AH, Kolve H, Ehlert K, Paulussen M, Vormoor J . Pharmacokinetic interaction between voriconazole and ciclosporin A following allogeneic bone marrow transplantation. J Antimicrob Chemother 2004; 53: 113–114.

    Article  CAS  PubMed  Google Scholar 

  182. Porter CC, Carver AE, Albano EA . Vincristine induced peripheral neuropathy potentiated by voriconazole in a patient with previously undiagnosed CMT1X. Pediatr Blood Cancer 2009; 52: 298–300.

    Article  PubMed  Google Scholar 

  183. Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT . Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Clin Pharmacol Ther 2006; 79: 362–370.

    Article  CAS  PubMed  Google Scholar 

  184. Schwiesow JN, Iseman MD, Peloquin CA . Concomitant use of voriconazole and rifabutin in a patient with multiple infections. Pharmacotherapy 2008; 28: 1076–1080.

    Article  CAS  PubMed  Google Scholar 

  185. Wexler D, Courtney R, Richards W, Banfield C, Lim J, Laughlin M . Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study. Eur J Pharm Sci 2004; 21: 645–653.

    Article  CAS  PubMed  Google Scholar 

  186. Sansone-Parsons A, Krishna G, Martinho M, Kantesaria B, Gelone S, Mant TG . Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus. Pharmacotherapy 2007; 27: 825–834.

    Article  CAS  PubMed  Google Scholar 

  187. Stone JA, Holland SD, Wickersham PJ, Sterrett A, Schwartz M, Bonfiglio C et al. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother 2002; 46: 739–745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Hebert MF, Townsend RW, Austin S, Balan G, Blough DK, Buell D et al. Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers. J Clin Pharmacol 2005; 45: 954–960.

    Article  CAS  PubMed  Google Scholar 

  189. Hebert MF, Blough DK, Townsend RW, Allison M, Buell D, Keirns J et al. Concomitant tacrolimus and micafungin pharmacokinetics in healthy volunteers. J Clin Pharmacol 2005; 45: 1018–1024.

    Article  CAS  PubMed  Google Scholar 

  190. FDA. Guidance for Industry. Bioanalytical Method Validation. 2001.

  191. Honour JW . Development and validation of a quantitative assay based on tandem mass spectrometry. Ann Clin Biochem 2011; 48: 97–111.

    Article  CAS  PubMed  Google Scholar 

  192. Denning DW, Tucker RM, Hanson LH, Stevens DA . Treatment of invasive aspergillosis with itraconazole. Am J Med 1989; 86: 791–800.

    Article  CAS  PubMed  Google Scholar 

  193. Denning DW, Tucker RM, Hanson LH, Hamilton JR, Stevens DA . Itraconazole therapy for cryptococcal meningitis and cryptococcosis. Arch Intern Med 1989; 149: 2301–2308.

    Article  CAS  PubMed  Google Scholar 

  194. Cartledge JD, Midgely J, Gazzard BG . Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis. J Clin Pathol 1997; 50: 477–480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Glasmacher A, Hahn C, Leutner C, Molitor E, Wardelmann E, Losem C et al. Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses 1999; 42: 443–451.

    Article  CAS  PubMed  Google Scholar 

  196. Jang SH, Colangelo PM, Gobburu JV . Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin Pharmacol Ther 2010; 88: 115–119.

    Article  CAS  PubMed  Google Scholar 

  197. Walsh TJ, Raad I, Patterson TF, Chandrasekar P, Donowitz GR, Graybill R et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007; 44: 2–12.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Roger Brüggemann for a critical review of the manuscript.

Author information

Authors and Affiliations

  1. Department of Microbiology, Mycology Reference Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK

    H R Ashbee

  2. Department of Haematology, St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, UK

    M H Gilleece

Authors
  1. H R Ashbee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M H Gilleece
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H R Ashbee.

Ethics declarations

Competing interests

HRA has received speakers fee, travel support or research funding from Pfizer, Gilead UK and Merck Ltd. MHG has received speakers fees or travel support from Pfizer, Gilead UK and Merck Ltd.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ashbee, H., Gilleece, M. Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics. Bone Marrow Transplant 47, 881–894 (2012). https://doi.org/10.1038/bmt.2011.146

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2011.146

Keywords

This article is cited by

Search

Advanced search

Quick links