title: A highly sensitive LC-MS/MS method for determination of ketoconazole in human plasma: Application to a clinical study of the exposure to ketoconazole in patients after topical administration.
abstract: A simple, rapid and highly sensitive LC-MS/MS method was developed and validated for the determination of ketoconazole in human plasma. Sample preparation was accomplished through a single step liquid-liquid extraction by ethyl acetate. The chromatography separation was carried out on a Hedera CN (150mm×2.1mm, 5μm) column with isocratic elution using acetonitrile and 10mM ammonium acetate containing 0.1% formic acid (45:55, v/v) as the mobile phase. The flow rate was 0.5mL/min. Detection was performed in the positive ion electrospray ionization mode using multiple reaction monitoring of the transitions of 531.2→489.3 and 286.1→217.1 for ketoconazole and letrozole (the internal standard), respectively. The method exhibited good linearity over the concentration range of 0.01-12ng/mL for ketoconazole. The intra- and inter-batch precision and accuracy of ketoconazole were all within the acceptable criteria. The method was successfully applied to a clinical study of the exposure to ketoconazole in Chinese seborrheic dermatitis patients after topical administration of two ketoconazole formulations of foam and lotion, respectively. The study results showed that there was little systemic absorption of ketoconazole in patients for the two formulations, and the ketoconazole foam and lotion are safe therapeutic drugs for seborrheic dermatitis patients.
authors.affiliation: Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Keli
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Chi
authors.affiliation: Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Shu
authors.affiliation: Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao Street, Nanjing 210042, China.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao Street, Nanjing 210042, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao Street, Nanjing 210042, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Tao
authors.affiliation: Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao Street, Nanjing 210042, China. Electronic address: mpc815@163.com.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Ma
authors.affiliation: Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: dinglidl@hotmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
mesh_terms: D000287:Administration, Topical; D000328:Adult; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D012628:Dermatitis, Seborrheic / Q000097:blood; D004355:Drug Stability; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077289:Letrozole; D059625:Liquid-Liquid Extraction; D009570:Nitriles / Q000097:blood; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014230:Triazoles / Q000097:blood; D055815:Young Adult
chemical_list: D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D007654:Ketoconazole
keywords: Foam; Ketoconazole; LC–MS/MS; Lotion; Systemic exposure; Topical administration