| Summary: | Abstract Background Itraconazole (ITZ), a triazole antifungal agent, is metabolized to hydroxy-ITZ (OH-ITZ), keto-ITZ (KT-ITZ), and N-desalkyl ITZ (ND-ITZ) by cytochrome P450 3A4. The pharmacokinetics of ND-ITZ remain largely unknown due to the lack of an accurate and reliable determination method. This study aimed to develop a simultaneous determination method for ITZ and its three major metabolites including ND-ITZ in human plasma using isocratic liquid chromatography coupled to tandem mass spectrometry and then apply the method in a clinical setting. Methods Plasma specimens were pretreated by protein precipitation with acetonitrile. The supernatant was separated on a 3-μm particle octadecyl silane column (75 × 2.0 mm I.D.) in an isocratic elution of acetonitrile and 5 mM ammonium acetate (pH 6.0) (57:43, v/v). The method was applied to 10 patients treated with oral ITZ. Results The calibration curves of ITZ, OH-ITZ, KT-ITZ, and ND-ITZ were linear over the concentration ranges of 15–1500, 15–1500, 1–100, and 1–100 ng/mL, respectively. The pretreatment recoveries and matrix factors were 90.1–102.2% and 99.1–102.7%. Their intra- and inter-assay accuracies and imprecisions were 94.1–106.7% and 0.3–4.4%. The plasma concentrations of ITZ, OH-ITZ, KT-ITZ, and ND-ITZ 12 h after dosing ranged from 32.5–1127.1, 19.0–1166.7, 1.1–5.4, and 3.5–28.3 ng/mL, respectively, in immunocompromised patients. Conclusions This study developed a simultaneous determination method for concentrations of ITZ and its three metabolites including ND-ITZ in a clinical setting.
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