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Antimicrobial Agents and Chemotherapy, May 2004, p. 1756-1762, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1756-1762.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Dose-Dependent Pharmacokinetics of Itraconazole after Intravenous or Oral Administration to Rats: Intestinal First-Pass Effect

Jee H. Shin, Ka Y. Choi, Yu C. Kim, and Myung G. Lee*

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Korea

Received 24 July 2003/ Returned for modification 1 December 2003/ Accepted 19 January 2004

The dose-dependent pharmacokinetics of itraconazole after intravenous (10, 20, or 30 mg/kg) and oral (10, 30, or 50 mg/kg) administration and the first-pass effects of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration at a dose of 10 mg/kg were evaluated in rats. After intravenous administration at a dose of 30 mg/kg, the area under the plasma concentration-time curve from time zero to infinity (AUC0-{infty}) was significantly greater than those at 10 and 20 mg/kg (1,090, 1,270, and 1,760 µg · min/ml for 10, 20, and 30 mg/kg, dose-normalized at 10 mg/kg). After oral administration, the AUC0-{infty} was significantly different for three oral doses (380, 687, and 934 µg · min/ml for 10, 30, and 50 mg/kg, respectively, dose-normalized at 10 mg/kg). The extent of absolute oral bioavailability (F) was 34.9% after an oral dose at 10 mg/kg. The AUC0-{infty} (or AUC0-8 h) values were comparable between intravenous and intraportal administration and between intragastric and intraduodenal administration, suggesting that the hepatic and gastric first-pass effects were almost negligible in rats. However, the AUC0-8 h values after intraduodenal and intragastric administration were significantly smaller than that after intraportal administration, approximately 30%, suggesting that the intestinal first-pass effect was approximately 70% of that of an oral dose of 10 mg/kg. The low F after oral administration of itraconazole at a dose of 10 mg/kg could be mainly due to the considerable intestinal first-pass effect.

* Corresponding author. Mailing address: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Korea. Phone: 822-880-7855. Fax: 822-889-8693. E-mail: leemg{at}snu.ac.kr.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1756-1762, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1756-1762.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Quinney, S. K., Galinsky, R. E., Jiyamapa-Serna, V. A., Chen, Y., Hamman, M. A., Hall, S. D., Kimura, R. E. (2008). Hydroxyitraconazole, Formed During Intestinal First-Pass Metabolism of Itraconazole, Controls the Time Course of Hepatic CYP3A Inhibition and the Bioavailability of Itraconazole in Rats. Drug Metab. Dispos. 36: 1097-1101 [Abstract] [Full Text]  


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