Improved blood–brain barrier distribution: Effect of borneol on the brain pharmacokinetics of kaempferol in rats by in vivo microdialysis sampling

Kaempferol (KA) exists in a variety of herbal medicines. In vitro and in vivo studies have focused on the anti-Alzheimer effect of KA. However, little is known about its brain pharmacokinetic profile. The accumulated amount of KA in brain is very low because of the protection of blood–brain barrier (BBB). Borneol (BO) is a classical aromatic refreshing traditional Chinese medicine and commonly used as an adjuvant component of traditional Chinese medicines (e.g. compound Danshen dropping pills) in the treatment of cardiovascular and cerebrovascular diseases. According to the basic theories of traditional Chinese medicine, BO is called an “upper guiding drug”, which can guide other components to the targeting tissues or organs in the upper part of the body, especially in the brain. The probes for blood and brain sampling were implanted within the jugular vein/right atrium and right hippocampus of SD rats, respectively. Rats were intravenous administered of KA (25 mg/kg) alone or combined with BO (15, 30 mg/kg) via caudal vein. The blood and brain microdialysates were collected every 15 min for 180 min and every 30 min for 180−300 min. A selective and sensitive high performance liquid chromatography–chemiluminescence method was developed for the determination of unbound KA in rat blood and brain microdialysates, which can be converted to their actual free-form concentrations based on the in vivo relative recoveries of KA across microdialysis probes. KA quickly crossed the BBB to enter the extracellular fluid of hippocampus and reached the maximum concentration of 0.11 μg/mL within 30 min. The brain bioavailability and brain delivery of KA evidently increased with the co-administration of 15 and 30 mg/kg of BO. The AUC0–inf of KA in brain increased 1.84 and 2.19 times, and the Cmax of KA in brain increased 2.09 and 3.18 times than that without BO, respectively. In addition, the brain-to-blood distribution ratio of KA increased by 48.68% and 57.97% compared with that without BO. However, no significant difference in the T1/2 of unbound KA in blood aserved between three groups. BO can enhance the BBB permeability and improve the transportation of KA to brain. The dose-dependent effect of BO on the brain pharmacokinetic parameters of KA was observed. This co-administration strategy can be designed to enhance the brain accumulation of other neuropsychiatric medications.