Integrated pharmacokinetic study of itraconazole and its active metabolite-hydroxyitraconazole in human

Abstract

Abstract: AIM: Hydroxyitraconazole (OH-ITZ) is the magor active metabolite of itraconazole (ITZ) which is the first-line antifungal drug and it has antifungal activity similar to ITZ. Forther more, the plasma concentration of OH-ITZ is higher than that of ITZ. Therefore, it can not be ignored that the pharmacokinetics of OH-ITZ effect on the clinical therapeutic effects. This study was designed to develop a sensitive and rapid LC-MS/MS method for direct determination of ITZ and OH-ITZ in human plasma and to study the integrated pharmacokinetics of ITZ and OH-ITZ in human. METHODS: ITZ, OH-ITZ andinternal standard (buspirone) were pretreated from plasma OH-ITZ in human using protein precipitation with acetonitrile/methanol(1∶1). Chromatographic separation was achieved on an Agilent Zorbax-C₁₈ column (2.1 mm×50 mm, 3.5 μm) using a step gradient program with the mobile phase of 0.1% formic acid aqueous solution and acetonitrile with 0.1% formic acid, at a flow-rate of 0.50 mL/min. Electrospray ionization (ESI) source was applied and operated in the positive ion mode. Multiple reaction monitoring (MRM) mode with the transitions of m/z 705 →m/z 392, m/z 721→m/z 408 and m/z 386→m/z 122 was performed to quantify ITZ, OH-ITZ and IS, respectively. RESULTS: The linear concentration ranges of calibration curves for ITZ and OH-ITZ were 0.50-500 ng/mL. The inter- or intra-day precision (RSD) was less than 12.4% and the accuracy (RE) was within±7.5%. Based on the AUC weighting coefficients integration approach, the integrated pharmacokinetic parameters were calculated. The holistic t_1/2 and AUC_0-∞ were of 19.5 hr and 5754 ng·h·mL^-1 in human plasma after oral administration of 200 mg itraconazole. CONCLUSION: The method is sensitive, rapid, convenient, using less plasma and is proved to be suitable for clinical pharmocokinetics of ITZ and OH-ITZ. The holistic pharmacokinetic properties of ITZ and OH-ITZ were described successfully.

Key words: itraconazole(ITZ), hydroxyitraconazole(OH-ITZ), liquid chromatography-tandem mass spectrometry, integrated pharmacokinetics

CLC Number:

R969

FU Shu-jun, FENG Li-min, SUN Lian-fu, LIU Chang-xiao, HE Xin. Integrated pharmacokinetic study of itraconazole and its active metabolite-hydroxyitraconazole in human[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(1): 56-63.

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