Pharmacokinetic studies of novel berberine derivatives with ultra-performance liquid chromatography–tandem mass spectrometry

• Development of a UPLC–MS/MS method for berberine and its derivatives in rat plasma.
• Its derivative B4 has increased Cmax (8-fold), t1/2 (2-fold), and AUC than berberine.
• Inversely, its derivative A4 has decreased Cmax, t1/2, and AUC than berberine, suggesting a tight structure-activity relationship of these compounds.
• Oral bioavailability of A4,B4, and berberine was 0.12%, 3.4% and 0.7%, respectively.
• Organ accumulation of B4 was intestine > liver > heart > kidney > lung > spleen > plasma, proving a deeply targeting property of B4.

An ultra-performance liquid chromatography with tandem mass spectrometric detection method was developed for the detection of berberine and its derivatives (A4, B4) in rat plasma and other organs. This validated method was successfully applied to our pharmacokinetic study of BBR derivatives in rats. At the same dose of administration, the Cmax of B4 was about eight times higher than BBR, and its half-life was approximately two times longer than BBR, according to the bigger areas under plasma concentration curves. Inversely, the pharmacokinetic parameter levels of A4 were all inferior to BBR, suggesting a tight structure-activity relationship of these compounds. Small dose of parenteral administration was used for the study of absolute oral bioavailability of A4, B4, and BBR, and the results calculated were 0.12%, 3.4% and 0.7%, respectively. The accumulations of B4 among all organs were intestine > liver > heart > kidney > lung > spleen > plasma, proving a deeply targeting property of B4, which met our experimental assumption. Together, the experimental results proved that compared with BBR and A4, the derivative B4 had higher absolute oral bioavailability and the ability of deeply targeting so that can be likely used in some organ-targeted diseases.