Determination of landiolol, an ultra-short-acting β1-receptor antagonist, in human plasma by liquid chromatography–tandem mass spectrometry

A method for the determination of landiolol, an ultra-short-acting β1-adrenoreceptor antagonist, in human plasma has been developed and validated. With the addition of pyridostigmine bromide to stabilize landiolol in the blood/plasma samples, and bisoprolol as internal standard, plasma samples were subjected to liquid–liquid extraction with diethyl ether:dicholoromethane (60:40, v/v) prior to assay by liquid chromatography–tandem mass spectrometry. Separation was performed on a TC-C18 column (150 mm × 4.6 mm, 5 μm) using a mobile phase of methanol:10 mM ammonium acetate containing 1% formic acid (65:35, v/v) in a run time of 3.5 min. Detection involved electrospray ionization in the positive ion mode followed by multiple reaction monitoring of the precursor-to-product ion transitions of landiolol at m/z 510.1 → 157.2 and bisoprolol at m/z 326.3 → 116.1. The method was linear over the concentration range 0.5–500 ng/ml with a lower limit of quantitation of 0.5 ng/ml. Intra- and inter-day precisions (as relative standard deviation, RSD) were <4.4% and <10.0%, respectively, with accuracy (as relative error, RE) <10.0%. The method was successfully applied to a clinical pharmacokinetic study involving a continuous infusion of landiolol hydrochloride to healthy Chinese volunteers.

► A novel method for determination of landiolol in plasma by LC–MS/MS was developed.
► Landiolol in blood/plasma samples is stabilized by pyridostigmine bromide.
► The plasma samples were prepared by liquid–liquid extraction.
► The LLOQ of the method is 0.5 ng/ml which is the lowest reported so far.
► The method was successfully applied to a clinical pharmacokinetic study of landiolol.