Determination of benzonatate and its metabolite in human plasma by HPLC-MS/MS: A preliminary pharmacokinetic study in healthy Chinese volunteers after oral administration of benzonatate soft capsule.
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Man J, Jiao F, Wang Y, Gu Y, Ding L, Shu C
Determination of benzonatate and its metabolite in human plasma by HPLC-MS/MS: A preliminary pharmacokinetic study in healthy Chinese volunteers after oral administration of benzonatate soft capsule.
J Pharm Biomed Anal. 2019 Sep 5;173:134-143. doi: 10.1016/j.jpba.2019.05.030. Epub 2019 May 16.
- PubMed ID
- 31129533 [ View in PubMed]
- Abstract
Benzonatate has been used as a non-narcotic oral antitussive drug for many years. Its pharmacokinetics has never been reported due to the technical difficulties in detecting benzonatate by mass spectrometry. However, its concentration can be extrapolated based on the concentration of its metabolite, 4-(butylamino)benzoic acid (BBA). In this study, two sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods were developed and fully validated for the determination of the original 4-(butylamino)benzoic acid (method B) and total 4-(butylamino)benzoic acid (containing the original 4-(butylamino)benzoic acid and 4-(butylamino)benzoic acid converted from benzonatate after collection, method A). For both methods, one-step protein precipitation by methanol was performed to extract analytes from the plasma samples. Chromatographic separation was done on an InfinityLab Poroshell 120 Phenyl Hexyl column (2.1mmx50mm, 2.7mum, Agilent) with initial mobile phase consisting of 5mM ammonium acetate containing 0.3% formic acid and acetonitrile (60:40, v/v) at a flow rate of 0.3mL/min. Quantification was achieved by multiple reaction monitoring (MRM) in electron spray ionization (ESI) positive mode with the transitions of m/z 194.2-->138.1 and 515.3-->497.3 for 4-(butylamino)benzoic acid and telmisartan (the internal standard), respectively. The two methods exhibited good linearity over the concentration range of 10-10000ng/mL. Both of the methods were successfully applied to the preliminary pharmacokinetic study in healthy Chinese volunteers after oral administration of benzonatate soft capsule at a single dose of 100mg. The results showed that 4-(butylamino)benzoic acid and benzonatate were rapidly absorbed and reached a maximum concentration (Cmax) of 1708+/-457ng/mL and 1063+/-460ng/mL, respectively. The half-life (t1/2) were 1.32+/-0.29h for 4-(butylamino)benzoic acid and 1.01+/-0.41h for benzonatate. The area under the curve from 0h to 10h (AUC0-10) for 4-(butylamino)benzoic acid and benzonatate were 2103+/-918ng/mL.h and 1097+/-559ng/mL.h, respectively. And the data was valuable for further clinical study.
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