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Development of a rapid LC-MS/MS assay to determine letrozole in human plasma and its application in a pharmacokinetic study after oral administration

Li Pengfei, Zhang Xi, Wang Shumin, Wang Jing, Liu Ziqi, Wang Chen, Tong Weihang, Liu Lihong

Acta Chromatographica

2022

Vol. 34, no. 2

179--184

Letrozole is one of the third generation aromatase inhibitors. It is suitable for the treatment of postmenopausal patients with advanced breast cancer and early treatment of breast cancer. It is necessary to develop a rapid, reliable, selective and sensitive LC–MS/MS assay to determine letrozole in human plasma to evaluate the clinical efficacy and adverse reactions with clinical pharmacokinetic and therapeutic drug monitoring. Separation was carried out on a Kromasil-C18 column using acetonitrile-water (55: 45, v/v) as mobile phase. Detection was carried out by multiple reaction monitoring on a 3200Qtrap mass spectrometry. The method needed one-step protein precipitation procedure only, and the cycle time was 2.5 min allowing 500–550 samples per day. It was linear within 0.30–50.00 ng/mL for plasma with the limit of detection (LOD) of 0.030 ng/mL. The intra- and inter-day RSD were 5.51–8.63%, 2.28–9.95% and the RE was 0.18–1.65%. The recovery rates of letrozole and internal standard for plasma were 89.30–98.55%. Letrozole was stable under all the conditions in the study. The method was sensitive enough to quantitate letrozole over a period of 288 h after giving a single oral dose of 2.5 mg–24 Chinese healthy volunteers. The absorption of letrozole was rapid with small individual difference, the tissue distribution of letrozole was more than that in blood, and the clearance was slow. Letrozole was similar to three-compartment model in vivo. Due to metabolism and excretion, the AUCs of letrozole varied greatly among individuals.

Evaluation of the pharmacokinetics of the simultaneous quantification of letrozole and palbociclib in rat plasma by a developed and validated HPLC–PDA

Al-Shehri Mona, Hefnawy Mohamed, Abuelizz Hatem, Alzamil Adeeba

Acta Chromatographica

2020

Vol. 32, no. 3

170--178

The US Food and Drug Administration (FDA) has affirmed the use of letrozole (LTZ combined with palbociclib (PLB) to treat breast malignant tumor growth in postmenopausal women. A straightforward and extremely sensitive reversed-phase high-performance liquid chromatography method with photodiode array detection (RP-HPLC–PDA) was created and validated for the simultaneous determination of LTZ and PLB in rat plasma. The parameters used to give the best separation were a C18 column (150 mm × 4.6 mm, 3.5 μm) as the stationary phase with an isocratic mobile phase composed of methanol–30 mM ammonium acetate at a ratio of 60:40 (v/v), pH = 5.5, a flow rate of 0.8 mL/min, and detection wavelengths of 240 and 220 nm for LTZ and PLB, respectively. The developed method was assessed by the FDA rules over a range of 10–600 ng/mL for LTZ and PLB. The mean of %recovery of LTZ and PLB extracted from rat plasma by acetonitrile-based deproteinization was 91.06 ± 2.73 and 90.30 ± 1.95%, respectively, and the limits of detection were 5 ng/mL for LTZ and 7 ng/mL for PLB in rat plasma. The mean values of Tmax and Cmax were 6 ± 0.00 h and 266.96 ± 21.23 ng/mL for LTZ and 4 ± 0.00 h and 508.75 ± 61.56 ng/mL for PBL, respectively, after intraperitoneal administration of both drugs to rats. The developed HPLC–PDA method was demonstrated to be robust and was effectively applied to study the pharmacokinetics of LTZ and PLB in rat plasma.