Pharmacokinetic Study and Tissue Distribution of Lorlatinib in Mouse Serum and Tissue Samples by Liquid Chromatography-Mass Spectrometry

摘要

In the present study, we developed and validated a rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS/ MS) method for the determination of lorlatinib in mouse serum and tissue samples, and such a method was successfully applied to investigate the pharmacokinetic study and tissue distribution of lorlatinib after oral administration. Samples were processed with methanol to precipitate protein and extract drugs, and Afatinib-d6 was used as the internal standard (IS). For LC-MS/MS analysis, compounds were separated on a C18 column by gradient elution (0.1% of formic acid and methanol) at 0.5 mL/min in the positive-ion mode with m/z 407.28 [M + H]~+ for lorlatinib and m/z 492.10 [M + H]~+ for IS. Good linearity was observed within the calibration ranges. Selectivity, accuracy (-6.42% to 8.84%), precision (1.69% to 10.98%), recoveries (91.4% to 115.0%), and matrix effect (84.2% to 110.6%) were all within the acceptable ranges. After oral administration, serum concentration of lorlatinib quickly achieved the maximal concentration (2,705.683 ± 539.779 μg/L) at 0.625 ± 0.231 h. The highest concentration was detected in the liver (3,153.93 ng/100 mg), followed by the stomach (2,159.92 ng/100 mg) and the kidney (548.83 ng/100 mg). In conclusion, a simple and rapid detection method was established and validated for determination of lorlatinib in blood and tissue samples of mouse. The pharmacokinetic study and tissue distribution of lorlatinib were successfully investigated using this method.