title: Simultaneous microdetermination of bosentan, ambrisentan, sildenafil, and tadalafil in plasma using liquid chromatography/tandem mass spectrometry for pediatric patients with pulmonary arterial hypertension.
abstract: A simultaneous, selective, sensitive, and rapid liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of bosentan, ambrisentan, sildenafil, and tadalafil in 50μL of human blood plasma. Diluted plasma samples were extracted using a solid-phase extraction procedure with 2% formic acid and methanol. The four drugs were separated by high-performance liquid chromatography using a C18 column and an isocratic mobile phase running at a flow rate of 0.2mL/min for 5min. The drugs were detected by a tandem mass spectrometer with electrospray ionization using deuterated compounds as internal standards. Calibration curves were generated over the linear concentration range of 2-1000ng/mL in plasma with a lower limit of quantification of 2ng/mL for all compounds. Finally, this validated method was applied to a clinical pharmacokinetic study in pediatric patients with pulmonary arterial hypertension (PAH) following the oral administration of PAH drugs. These results indicate that this method is suitable for assessing the risk/benefit of combination therapy in the pediatric population and useful for therapeutic drug monitoring for PAH treatment.
authors.affiliation: Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Tomatsuri
authors.affiliation: Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; Department of Pharmacy, Shizuoka Children's Hospital, 860, Urushiyama, Aoi-ku, Shizuoka, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Hirai
authors.affiliation: Department of Pediatric Cardiology, Shizuoka Children's Hospital, 860, Urushiyama, Aoi-ku, Shizuoka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Todoroki
authors.affiliation: Department of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Toyo'oka
authors.affiliation: Department of Drug Evaluation & Informatics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. Electronic address: itohk@u-shizuoka-ken.ac.jp.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000077300:Bosentan; D002243:Carbolines / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid / Q000379:methods; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood*; D007223:Infant; D008297:Male; D010666:Phenylpropionates / Q000097:blood*; D010879:Piperazines / Q000097:blood*; D011687:Purines / Q000097:blood; D011724:Pyridazines / Q000097:blood*; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000097:blood*; D013450:Sulfones / Q000097:blood*; D000068581:Tadalafil; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D002243:Carbolines; D010666:Phenylpropionates; D010879:Piperazines; D011687:Purines; D011724:Pyridazines; D013449:Sulfonamides; D013450:Sulfones; D000068581:Tadalafil; D000068677:Sildenafil Citrate; C467894:ambrisentan; D000077300:Bosentan
keywords: Ambrisentan; Bosentan; LC–MS/MS; Sildenafil; Tadalafil