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J Pharm Biomed Anal. 2014 Feb;89:227-32. doi: 10.1016/j.jpba.2013.11.007. Epub 2013 Nov 15.

Simultaneous microdetermination of bosentan, ambrisentan, sildenafil, and tadalafil in plasma using liquid chromatography/tandem mass spectrometry for pediatric patients with pulmonary arterial hypertension.

Author information

1
Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
2
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.
3
Department of Pediatric Cardiology, Shizuoka Children's Hospital, 860, Urushiyama, Aoi-ku, Shizuoka, Japan.
4
Department of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
5
Department of Drug Evaluation & Informatics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
6
Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. Electronic address: itohk@u-shizuoka-ken.ac.jp.

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.

KEYWORDS:

Ambrisentan; Bosentan; LC–MS/MS; Sildenafil; Tadalafil

PMID:
24309556
DOI:
10.1016/j.jpba.2013.11.007
[Indexed for MEDLINE]

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