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A Highly Sensitive LC-MS/MS Method for the Quantification of Cabergoline in Human Plasma

04 Apr 2018

Cabergoline: Chemical Structure Introduction

Cabergoline (brand names: Caberlin, Dostinex and Cabaser), an ergot derivative, is a potent dopamine 2 receptor agonist. Rat studies have shown that Cabergoline has a direct inhibitory effect on pituitary lactotroph (prolactin) cells. It is frequently used as a first-line agent in the management of prolactinomas due to its higher affinity for D2 receptors, less severe side effects, and more convenient dosing schedule compared to the older bromocriptine. Published literature report that the maximum plasma concentration (Cmax) for the 0.5 mg dose ranged from 10 pg/mL to 22 pg/mL, hence a selective and highly sensitive method at a lower limit of quantification (LLOQ) of around 0.5 pg/mL is necessary to meet the regulatory requirement of having an LLOQ at least 1/20th of the Cmax. This was accomplished in the new LC-MS/MS method developed at our end.

Method

Briefly, the method of Cabergoline quantification involves liquid-liquid extraction using Cabergoline-d6 as an internal standard (ISTD). Chromatographic separation was achieved on C8 column with a mobile phase consisting of ammonium formate buffer and organic mixture with a gradient time program, and a total run-time of 5.5 minutes. Detection was carried out in the positive electro-spray ionization mode using multiple reaction monitoring (MRM) transitions of 452.300?381.200 for Cabergoline and 458.300?387.400 for Cabergoline-d6 (ISTD). Due to the high sensitivity requirement of the assay, special precautions were taken at the time of sample processing and analysis. Also, co-eluting peaks were separated using gradient time program. Moreover, due to sticky nature of the drug, carryover problem was observed, which was resolved by appropriate selection of the rinsing solution.

The method was developed in terms of linearity, stability, carry-over effect, reinjection reproducibility, precision and accuracy, and selectivity. This new method has a linearity range from 0.5 to 80 pg/mL. Cabergoline is found to be stable in plasma under the assay condition. The method exhibited good precision and accuracy, with precision better than 6.2% and accuracy greater than 92.3%. Also, there was no significant matrix effect observed in normal human lots.

The developed method is suitable for the analysis of samples from a single oral dose of 0.5 mg and 1.0 mg administration to humans, and will be applied to analyze study samples.

To conclude, a selective, simple, precise and accurate, and highly sensitive LC-MS/MS method is now available for the quantification of Cabergoline in human plasma.