QUANTIFICATION OF LETROZOLE IN HUMAN PLASMA USING LC-(–)ESI-MS/MS WITH D₄-LETROZOLE AS INTERNAL STANDARD: APPLICATION IN A PHARMACOKINETIC STUDY

Abstract

To investigate the pharmacokinetics of letrozole in healthy postmenopausal Chinese women, a rapid, selective, and sensitive liquid chromatography–tandem mass spectrometric method in negative ionization mode was developed and validated to determine letrozole in human plasma using d₄-letrozole as the internal standard (IS). Following protein precipitation, effective chromatographic separation was accomplished on a Capcell PAK C₁₈ MG column (100 mm × 4.6 mm, 5 µm) with a mobile phase consisting of methanol–10 mM ammonium acetate (65:35, v/v) at a flow rate of 0.6 mL/min. The running time was 4.0 min. The detection of the analyte and IS was carried out in selective reaction monitoring mode via negative electrospray ionization interface. The method was linear over concentrations ranging from 0.40 ng/mL to 50.0 ng/mL. The lower limit of quantification was 0.40 ng/mL, which allowed the measurement of letrozole concentration up to 240 hr after oral administration. The intraday and interday precisions were less than 12.9% in terms of the relative standard deviation, and the accuracy was within ±7.4% in terms of the relative error. Finally, this validated method was successfully applied to the clinical pharmacokinetic study after a single oral administration of 2.5 mg letrozole to 20 healthy, postmenopausal Chinese women.

Keywords:

• human plasma
• LC-MS/MS
• letrozole
• negative ionization mode
• pharmacokinetics
• quantification

Notes

RSD: relative standard deviation ; RE: relative error; SD: standard deviation.

RSD: relative standard deviation, RE: relative error, SD: standard deviation.