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Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo.

Publication ,  Journal Article
Templeton, IE; Thummel, KE; Kharasch, ED; Kunze, KL; Hoffer, C; Nelson, WL; Isoherranen, N
Published in: Clin Pharmacol Ther
January 2008

Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.

Duke Scholars

Published In

Clin Pharmacol Ther

DOI

EISSN

1532-6535

Publication Date

January 2008

Volume

83

Issue

1

Start / End Page

77 / 85

Location

United States

Related Subject Headings

  • Pharmacology & Pharmacy
  • Models, Biological
  • Male
  • Liver
  • Itraconazole
  • Humans
  • Glucuronides
  • Female
  • Enzyme Inhibitors
  • Drug Interactions
 

Citation

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Templeton, I. E., Thummel, K. E., Kharasch, E. D., Kunze, K. L., Hoffer, C., Nelson, W. L., & Isoherranen, N. (2008). Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo. Clin Pharmacol Ther, 83(1), 77–85. https://doi.org/10.1038/sj.clpt.6100230
Templeton, I. E., K. E. Thummel, E. D. Kharasch, K. L. Kunze, C. Hoffer, W. L. Nelson, and N. Isoherranen. “Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo.Clin Pharmacol Ther 83, no. 1 (January 2008): 77–85. https://doi.org/10.1038/sj.clpt.6100230.
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 Jan;83(1):77–85.
Templeton, I. E., et al. “Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo.Clin Pharmacol Ther, vol. 83, no. 1, Jan. 2008, pp. 77–85. Pubmed, doi:10.1038/sj.clpt.6100230.
Templeton IE, Thummel KE, Kharasch ED, Kunze KL, Hoffer C, Nelson WL, Isoherranen N. Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo. Clin Pharmacol Ther. 2008 Jan;83(1):77–85.
Journal cover image

Published In

Clin Pharmacol Ther

DOI

EISSN

1532-6535

Publication Date

January 2008

Volume

83

Issue

1

Start / End Page

77 / 85

Location

United States

Related Subject Headings

  • Pharmacology & Pharmacy
  • Models, Biological
  • Male
  • Liver
  • Itraconazole
  • Humans
  • Glucuronides
  • Female
  • Enzyme Inhibitors
  • Drug Interactions