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.
��ٻ, Ѧ����, ֧��Ȼ, ��ӱ, ��ռ��. ��������̹�Լװ������ڴ����������յ�Ӱ�켰��ػ����о�[J]. �й�ҩѧ��־, 2018, 53(15): 1285-1289.
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.
LI Y, DENG S, ZHAO Y, et al. Smilax glabra Rhizoma affects the pharmacokinetics and tissue distribution of methotrexate by increasing the P-glycoprotein mRNA expression in rats after oral administration[J]. Mol Med Report,2017,16(5):7633-7640.
ZAJC AVRAMOVIC M, DOLZAN V, TOPLAK N, et al. Relationship between polymorphisms in methotrexate pathway genes and outcome of methotrexate treatment in a cohort of 119 patients with juvenile idiopathic arthritis[J]. J Rheumatol, 2017,44(8):1216-1223.
DE MARCO G C, HELLIWELL P, MCGONAGLE D, et al. The GOLMePsA study protocol: an investigator-initiated, double-blind, parallel-group, randomised, controlled trial of GOLimumab and methotrexate versus methotrexate in early diagnosed psoriatic arthritis using clinical and whole body MRI outcomes[J]. BMC Musculoskelet Disord, 2017, 18(1):303.
LI Y, WANG Y, LIN D, et al. A study on pharmacokinetics of high dose methotrexate (HD-MTX)in adults with acute lymphoblastic leukemia[J]. Oncol Prog(��֢��չ),2015,13(1):100-104.
YAN B C, SHEN H, ZHANG Y, et al. The antiepileptic drug levetiracetam promotes neuroblast differentiation and expression of superoxide dismutase in the mouse hippocampal dentate gyrus via PI3K/Akt signalling[J]. Neurosci Lett, 2017, 662:84-90.
VERMA A, SRIVASTAVA D, KUMAR A, et al. Levetiracetam in migraine prophylaxis: a randomized placebo-controlled study in a rural medical institute in northern India[J]. Clin Neuropharmacol, 2013, 36(6):193-197.
WANG M, JIANG L, TANG X. Levetiracetam is associated with decrease in subclinical epileptiform discharges and improved cognitive functions in pediatric patients with autism spectrum disorder[J]. Neuropsychiatr Dis Treat, 2017, 31(13):2321-2326.
REEVES D, DIDOMINICK S, FINN S, et al. Methotrexate elimination when coadministered with levetiracetam[J]. Ann Pharmacother, 2016, 50(12):1016-1022.
LIU Q. The molecular pharmacokinetic mechanisms of puerarin on methotrexate with the transporters-mediated pharmacokinetics, renal toxicity in rats and multidrug resistance in K562/ADR cells [D]. Dalian: Dalian Medical University,2014.
CONWAY R, CAREY J J. Risk of live disease in methotrexate treated patients[J]. World J Hepatol, 2017, 9(26):1092-1100.
QIAN X, LI L K, WANG Q S, et al. Research progress of high dose methotrexate-calcium folinate to rescue children with acute lymphoblastic leukemia[J]. Chin Hosp Pharm J(�й�ҽԺҩѧ��־),2016,36(18):1613-1618.
YUAN Z, XU J, CHOU J C. Drug interaction between omeprazole and methotrexate:a case report and a review of the literature[J]. Chin J New Drug(�й���ҩ��־),2016,25(7):835-840.
LI N Z. Study of uptake transport drug-drug interaction between activated metabolite of rhein and methotrexate on hoAT3[D]. Nanjing: Southeast University(���ϴ�ѧ),2016.
XIAO B W, HU Q H, LIU C P, et al. Effect of micromolecular hydrophilic extract from vingar-baked bupleuri radix on pharmacokinetics of methotrexate[J]. Chin J Exp Tradit Med Form(�й�ʵ�鷽��ѧ��־), 2015, 21(16):76-78.
KONG M. Role of multidrug resistance gene and P-glycoprotein in predicting efficacy of antiepileptic drugs in children [D]. Chongqing: Medical University of Chongqing(����ҽ�ƴ�ѧ),2013.
PANG L, LIU L M, ZHAO L M. Research progress in influence factors of excretion delay of high-dose methotrexate[J]. Chin Pharm J(�й�ҩѧ��־), 2013, 48(22):1892-1896.