Absorption, first-pass metabolism, and disposition of itraconazole in rats

This study examined the pharmacokinetic disposition, oral absorption and he patic extraction of itraconazole and its active metabolite, hydroxyitracona zole, in rats. After i.v injection, serum itraconazole concentrations decre ased biexponentially, with an average terminal elimination half-life, volum e 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 ab solute bioavailability of 16.6%. The metabolite to parent drug area under t he 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 de termined 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 avail able itraconazole that was metabolized to hydroxyitraconazole was 21.0% and 76.0% after i.v. and oral administration, respectively. In summary, this s tudy is the first reporting the hepatic extraction of itraconazole and the i.v. disposition characteristics of hydroxyitraconazole in rats. Itraconazo le is a drug with a low hepatic extraction ratio and its systemic clearance appears to be largely accounted for by hepatic metabolism.