Novel LC‐MS/MS Method for Quantification of Famotidine and Metoprolol and Application to Pharmacokinetic Interaction

ABSTRACT A rapid and sensitive LC‐MS/MS method was developed and validated to simultaneously determine famotidine (FAM) and metoprolol (MET) in rat plasma and applied to study the pharmacokinetic drug–drug interaction between these two drugs in rats. In this method, D4‐famotine (D4‐FAM) and D6‐metoprolol (D6‐MET) were used as the internal standard and methanol protein precipitation method was used for sample preparation. After extraction, the samples were carried on an Agilent Gemini‐NX C 18 column and subjected to a gradient elution process using a mixture of methanol and water containing 0.1% formic acid at a flow rate of 0.4 mL/min within 8 min. The monitored transitions were m/z 338.1 → 189.1 for FAM, 268.2 → 116.1 for MET, 342.1 → 190 for D4‐FAM, and 274.2 → 122.1 for D6‐MET. The analytes had good linearity in the range of 1–200 ng/mL for FAM and 1–400 ng/mL for MET, with the lower limit of quantitation of 1 ng/mL for both drugs. The validated method was verified to meet the determination requirements of biological samples. It was the first time to study the pharmacokinetics interaction between FAM and MET successfully, which would be necessary and beneficial to explore the clinical safety and efficacy of the combination of these two drugs in the treatment of HF.