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Graphical abstract Figure. No Caption available. HighlightsThe pharmacokinetics of BBR and its derivatives including 8‐cetylberberine (8‐BBR‐C16) in rat plasma was studied by high performance liquid chromatography (HPLC).The excretion of 8‐BBR‐C16 in rat urine and feces were quantified by HPLC after purification by solid‐phase extraction.The main metabolites in rat urine were identified by liquid chromatography/tandem mass spectrometry (LC/MS/MS) with electrospray ionization. ABSTRACT Berberine (BBR) is a bioactive plant ingredient derived from the roots and bark of Berberis aristata and Coptis chinensis and has a wide variety of pharmacological effects. 8‐cetylberberine (8‐BBR‐C16) is the berberine (BBR) derivative reconstructed from adding octadecyl at C‐8 of BBR to enhance its activity. This study presents a reliable method for the determination of BBR and 8‐BBR‐C16 in rat plasma, urine and feces. BBR and 8‐BBR‐C16 were determined by HPLC‐UV after liquid‐liquid extraction for plasma samples, and solid‐phase extraction for urinary and fecal samples. The method was linear over the concentration range of 10‐300 ng·ml−1 for the plasma samples, 25‐2000 ng·ml−1 for the urinary samples, and 100‐2000 ng·g−1 for the fecal samples. Furthermore, a metabolic investigation on urine was performed by LC/MS/MS analysis to identify the structures of 8‐BBR‐C16 metabolites by full scan and product ion scan. Adult Sprague‐Dawley rats were divided into two groups. In the control group, rats received 80 mg·kg−1 BBR, and in the drug‐treated group, rats received 80 mg·kg−1 8‐BBR‐C16. The results indicate that there were significant differences in the pharmacokinetic parameters and in the accumulated excretion levels between the control group and the drug‐treated group. The Cmax and AUC0‐t of 8‐BBR‐C16 were 2.8 and 12.9 times higher than those of BBR, and the relative bioavailability of BBR to 8‐BBR‐C16 was 7.7%. The total excretion amount through the urine and feces of 8‐BBR‐C16 was 76.9%, but that of BBR was only 20.5%. Additionally, 8‐BBR‐C16 was metabolized in rat urine with phase I demethylation and phase II glucuronidation or sulfation.