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In this study, a simple, sensitive, and rapid analytical method was developed by ultra-performance liquid chromatography (UPLC) coupled with tandem quadrupole mass spectrometry (MS) for the determination of nootkatone in normal and chronic kidney disease (CKD) rat plasma using clarithromycin as internal standard. After sample preparation by simple liquid–liquid extraction, chromatography was performed on an Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 mm particle size) using gradient elution with the mobile phase composed of acetonitrile and water acidified with 0.1% (v/v) formic acid. Detection was achieved by electrospray ionisation MS under the multiple selective reaction monitoring mode. The linear range was 0.01‒500 ng/mL with the square regression coefficient (r) of 0.9975. The lower limit of quantification was 0.01 ng/mL. The intra- and inter-day precision was under 5% and the stability accuracy was between 3.6 and 7.0%. The average recoveries from spiked plasma samples were >83% and matrix effect was over 81%. The developed method was successfully applied to the pharmacokinetic study of nootkatone in normal and CKD rats after an oral administration of 50 mg/kg nootkaone. The results showed the cmax and area under curve of nootkaone were greatly decreased, meanwhile Vd/F and t1/2 were markedly increased in CKD rats. The pharmacokinetic characteristics of nootkatone in rats were significantly altered in CKD rats. [ABSTRACT FROM AUTHOR]