Effect of Levetiracetam on Absorption of Methotrexate in Rats and Related Mechanism
LI Qian1, XUE Chao-jun2, ZHI Xu-ran2, LI Ying1, DONG Zhan-jun1,2*
1. Graduate School of Hebei Medical University, Shijiazhuang 050017, China; 2. Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050051, China;
Abstract��OBJECTIVE To study the effect of levetiracetam on the absorption of methotrexate in rats and related mechanisms, and provide reference for clinical rational use of two drugs. METHODS ��Pharmacokinetic study: Sprague Dawley (SD) Rats (250��20)g were randomly divided into control group and experimental group, 5 rats in each group, administered by intragastric administration. At the design time point, blood was taken from the fundus venous plexus and centrifuged. Supernatant plasma for detection. ��The intestine experiment was performed in vitro: the rat 10 cm jejunum was taken and the intestinal segment was gently inverted with a capillary tube, and the intestinal anal side was ligated. After the 1 mL KRB buffer was added to the inverted intestinal lumen, the intestinal sac was placed vertically into the drug-containing solution. ��Caco-2 Cells uptake experiments: The Caco-2 cells were inoculated in a 24-well plate for 15 days and then subjected to an uptake experiment. After the incubation for 30 minutes, the cells were stopped for uptake and washed, and the cells were lysed for the detection of methotrexate and protein. Calculate the amount of drug intake. RESULTS ��The main pharmacokinetic parameters of control group and experimental group were as follows: ��max(ng��mL-1): 28.6��3.04��54.33��13.97; tmax(min): 50��8.32��70��7.32; AUC0-t(ng��min��mL-1): 8 230��2 274�� 15 003��3 359; AUC0-��(ng��min��mL-1): 8 450��2 125��15 108��3 371; CL(mL-1��min��kg-1): 161.8��27.6�� 90.43��13.76. In the experimental group, the ��max, tmax, AUC0-t and AUC0-�� values of methotrexate increased, and the CL value descreased. The difference was statistically significant. ��Compared with the control group, levetiracetam in the experimental group significantly increased the drug concentration of the methotrexate on the serosal side of the intestine, and its effect was time-dependent. ��Verapamil, digoxin and levetiracetam increased the uptake of methotrexate in the Caco-2 cells, and the effect of levetiracetam was dose-dependent. CONCLUSION When methotrexate and levetiracetam were combined, the drug interactions mediated by the efflux transporter P glycoprotein in the intestinal tract. Methotrexate reduces efflux in the body, increases absorption, and increases plasma concentration. It is suggested that the dose of methotrexate should be adjusted when the combination of methotrexate and levetiracetam, and blood concentration should be monitored if necessary.
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LI Qian, XUE Chao-jun, ZHI Xu-ran, LI Ying, DONG Zhan-jun. Effect of Levetiracetam on Absorption of Methotrexate in Rats and Related Mechanism. Chinese Pharmaceutical Journal, 2018, 53(15): 1285-1289.
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2018, Vol. 53 
