Effect of Verapamil on the Brain Pharmacokinetics of Amitriptyline and Nortriptyline in Mice

OBJECTIVE To study the influence of verapamil on the brain pharmacokinetics of amitriptyline(AMI) and nortriptyline(NOR) in mice. METHODS Kunming mice were equally divided into two groups by completely random design. Mice in each group were injected intraperitoneally with saline or verapamil(4 mg·kg^-1) twice a day. After 3 days, blood samples were collected at 5, 15, 30, 60, 90, 120, 180, 270, 360 min after AMI injected. Brain samples were removed after blood collecting and stored in liquid nitrogen. The whole AMI and NOR concentration in blood and brain samples were determined by HPLC-MS, the WinNonlin6.1 software was used to calculate the pharmacokinetics parameters. RESULTS Compared with the control group, the AUC of amitriptyine and NOR in verapamil group were increased by 1.9, 2.0 fold in plasma and 3.3, 3.5 fold in brain, respectively; the brain-to-plasma concentration ratio of amitriptyine and NOR were also increased by 1.4, 1.9 fold in verapamil group. CONCLUSION It is very likely that AMI and NOR are both P-gp substrates. Compared with AMI, NOR may have a better affinity to P-gp. Verapamil is a good inhibitor of both CYP and P-gp, it can also lead to a great enhancement of the concentration of AMI and increase the brain-to-plasma concentration ratio of AMI significantly.