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

Abstract

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 (AUC 0-ؕ ) was significantly greater than those at 10 and 20 mg/kg (1,090, 1,270, and 1,760 g ⅐ min/ml for 10, 20, and 30 mg/kg, dose-normalized at 10 mg/kg). After oral administration, the AUC 0-ؕ was significantly different for three oral doses (380, 687, and 934 g ⅐ min/ml for 10, 30, and 50 mg/kg, respectively, dosenormalized at 10 mg/kg). The extent of absolute oral bioavailability (F) was 34.9% after an oral dose at 10 mg/kg. The AUC 0-ؕ (or AUC 0-8 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 AUC 0-8 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.The pharmacokinetics of itraconazole after oral administration to humans (10-12), rats (11,22,31), and rabbits, cats, and dogs (11) have been reported; however, data on the pharmacokinetics after intravenous administration to humans (12), dogs (11), and rats (22, 31) are scarce. It has been reported (12) that after oral administration of itraconazole to humans, the values for the area under the plasma concentration-time curve from time zero to infinity (AUC 0-ϱ ) for the drug were dose dependent (increased in proportion to dose increases); 50, 100, and 200 mg by capsule after a meal and 100 and 200 mg by capsule after breakfast. However, the dose-dependent pharmacokinetics of itraconazole after intravenous administration and the first-pass effects of the drug have not been reported. It has been reported (31) that the hepatic first-pass effect of itraconazole was estimated to be 18.5% in rats.The purpose of this paper is to report the dose-dependent pharmacokinetics of itraconazole after intravenous (at doses of 10, 20, and 30 mg/kg) and oral (at doses of 10, 30, and 50 mg/kg) administration to rats and the intestinal first-pass effect of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration (at a dose of 10 mg/kg) to rats. MATERIALS AND METHODSChemicals. Sporanox intravenous solution (10 mg/ml as itraconazole as a solution in hydroxylpropyl-␤-cyclodextrin [HP-␤-CD], sorbitol, propylene glycol, HCl, NaOH, and water for injection; lot no. 01-D01A-IW), Spor...

Hydroxyitraconazole, Formed During Intestinal First-Pass Metabolism of Itraconazole, Controls the Time Course of Hepatic CYP3A Inhibition and the Bioavailability of Itraconazole in Rats

“…The AUC of ITZ after intragastric and intraduodenal administration was significantly smaller compared with intraportal administration, suggesting substantial intestinal first-pass metabolism of ITZ in rats. However, Shin et al (2004) found that the plasma concentration time course of ITZ following a 30-min intraportal infusion of 10 mg/kg was similar to that seen after intravenous infusion suggesting little, if any, hepatic firstpass metabolism of ITZ. This stands in marked contrast to the results of Yoo et al and to our results and may be attributable to the nonphysiologic conditions that were present in the studies by Shin et FIG.…”

“…Dose-dependent pharmacokinetics of ITZ have been described in both rats (Yoo et al, 2000;Shin et al, 2004) and humans (Heykants et al, 1989;Templeton et al, 2008). The concentration-and timedependent clearance and bioavailability of ITZ has been attributed to the inhibition of CYP3A by ITZ and the metabolites that are sequentially formed by CYP3A (Isoherranen et al, 2004;Templeton et al, 2008).…”

“…The time course for hepatic CYP3A inhibition may also reflect a contribution from keto-itraconazole and N-desalkyl-itraconazole, if these inhibitory metabolites are also formed from OH-ITZ by intestinal CYP3A. Shin et al (2004) reported a dose-dependent decrease in ITZ clearance in male Sprague-Dawley rats. The AUC of ITZ after intragastric and intraduodenal administration was significantly smaller compared with intraportal administration, suggesting substantial intestinal first-pass metabolism of ITZ in rats.…”

“…Itraconazole (ITZ), an orally active triazole antifungal agent, exhibits dose-dependent first-pass metabolism and nonlinear pharmacokinetics in both humans and rats (Hardin et al, 1988;Heykants et al, 1989;Yoo et al, 2000;Shin et al, 2004). Hydroxyitraconazole (OH-ITZ) is a major metabolite that is formed by CYP3A and has antifungal activity similar to ITZ (Heykants et al, 1989;Poirier and Cheymol, 1998).…”

“…Drug disposition studies can be conducted in awake, free-moving animals that have fully recovered from surgery and anesthesia and have regained their preoperative weight. Simultaneous sampling allows us to quantify the precise time course of changes in such pharmacokinetic parameters as clearance and hepatic extraction ratio.Itraconazole (ITZ), an orally active triazole antifungal agent, exhibits dose-dependent first-pass metabolism and nonlinear pharmacokinetics in both humans and rats (Hardin et al, 1988;Heykants et al, 1989;Yoo et al, 2000;Shin et al, 2004). Hydroxyitraconazole (OH-ITZ) is a major metabolite that is formed by CYP3A and has antifungal activity similar to ITZ (Heykants et al, 1989;Poirier and Cheymol, 1998).…”