Absorption, First-Pass Metabolism, and Disposition of Itraconazole in Rats.

Abstract

This study examined the pharmacokinetic disposition, oral absorption and hepatic extraction of itraconazole and its active metabolite, hydroxyitraconazole, in rats. After i.v. injection, serum itraconazole concentrations decreased biexponentially, with an average terminal elimination half-life, volume of distribution and systemic clearance of 4.9 h, 6.0 l/kg and 14.2 ml/min/kg, respectively. When given orally, its absorption was low, with a mean absolute bioavailability of 16.6%. The metabolite to parent drug area under the curve (AUC) ratio was higher after oral administration compared with i.v. injection (mean ratio, 2.7 vs. 0.9). The hepatic drug extraction ratio determined after femoral and portal vein administration averaged 18.5%. When hydroxyitraconazole was injected i.v., the elimination half-life, volume of distribution and systemic clearance of itraconazole averaged 10.0 h, 2.4 l/kg and 3.4 ml/min/kg, respectively. The fraction of the systemically available itraconazole that was metabolized to hydroxyitraconazole was 21.0% and 76.0% after i.v. and oral administration, respectively. In summary, this study is the first reporting the hepatic extraction of itraconazole and the i.v. disposition characteristics of hydroxyitraconazole in rats. Itraconazole is a drug with a low hepatic extraction ratio and its systemic clearance appears to be largely accounted for by hepatic metabolism.

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

“…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).…”

“…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).…”

A vaginal drug delivery model

“…The concentration of itraconazole in SLN and in the ultra-filtrate (free drug) was analyzed by a slight modification of a validated HPLC method (Yoo et al, 2000), with an accuracy of 95.5%, a precision of 6.7%, a regression coefficient of 0.998, a limit of detection 5.6 ng/ml, and a limit of quantification of 16.4 ng/ml. The instrumental parameters were according to our previous reports (Mirza et al, 2012).…”

“…A 5 ml aliquot of sample was withdrawn at regular time intervals, filtered, and assayed. The level of itraconazole in the media was estimated using the previously reported HPLC method (Yoo et al, 2000).…”