Effects of verapamil for phenytoin distribution in rat model with mesial temporal lobe epilepsy_Journal of Epilepsy

Authors：

FANG Ziyan ^1,2 , WU Fengchun ^1,2 , CHEN Shuda ³ , QIN Jiaming ⁴ ,  NING Yuping ^1,2 ,  ZHOU Liemin ^3,4

1. Department of Neurology, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou 510370, China;
2. Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou 510370, China;
3. Department of Neurology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China;
4. Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China;

Corresponding author：

NING Yuping, Email: ningjeny@126.com; ZHOU Liemin, Email: lmzhou56@163.com

Keywords：

Mesial temporal lobe epilepsy; Verapamil; Phenytoin; P-glycoprotein; Drug-resistant epilepsy; Microdialysis; Rats

DOI：

10.7507/2096-0247.20190029

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Objective In order to evaluate that whether the P-glycoprotein-inhibitor verapamil (VPM) could effect the distribution of antiepileptic drug phenytoin (PHT) in a rat model of mesial temporal lobe epilepsy (MTLE).Methods The rat models of MTLE were induced by li-pilocarpine and were randomly divided into two groups (PHT group and VPM+PHT treatment group) to compare the PHT distribution in brain, liver and kidney. Brain dialysate samples were collected by microdialysis technology. And the analysis of samples for PHT concentration was performed by high performance liquid chromatography (HPLC). The comparisons were carried out by t test (or Wilcoxon test).Results In VPM+PHT treatment group, 4 out of 9 rats were dead within 30 minutes after drug administration. The significantly decreased area under the curve (AUC) ratio of brain/plasma in VPM+PHT group was 0.11±0.06 when compared with PHT group 0.21±0.02 (t=3.237, P=0.025), while there were no significant differences in ratios of liver/plasma ［PHT (1.12±0.37) vs. VPM+PHT (0.99±0.27), Z=−0.490, P=0.624］ and kidney/plasma ［PHT (0.74±0.16) vs. VPM+PHT (0.49±0.26), t=1.872, P=0.103］ between two groups.Conclusions The P-glycoprotein-inhibitor VPM significantly decreased PHT level in brain of rat with MTLE.

Citation： FANG Ziyan, WU Fengchun, CHEN Shuda, QIN Jiaming, NING Yuping, ZHOU Liemin. Effects of verapamil for phenytoin distribution in rat model with mesial temporal lobe epilepsy. Journal of Epilepsy, 2019, 5(3): 165-169. doi: 10.7507/2096-0247.20190029 Copy

1.	Arroyo S, Brodie MJ, Avanzini G, et al. Is refractory epilepsy preventable? Epilepsia, 2002, 43(4): 437-444.
2.	Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med, 2000, 342(5): 314-319.
3.	Kwan P, Brodie MJ. Definition of refractory epilepsy: defining the indefinable? Lancet Neurol, 2010, 9(1): 27-29.
4.	Regesta G, Tanganelli P. Clinical aspects and biological bases of drug-resistant epilepsies. Epilepsy Res, 1999, 34(2-3): 109-122.
5.	Luna-Tortos C, Fedrowitz M, Loscher W. Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology, 2008, 55(8): 1364-1375.
6.	Luna-Tortos C, Rambeck B, Jurgens UH, et al. The antiepileptic drug topiramate is a substrate for human P-glycoprotein but not multidrug resistance proteins. Pharm Res, 2009, 26(11): 2464-2470.
7.	Volk HA, Loscher W. Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures. Brain, 2005, 128(Pt 6): 1358-1368.
8.	Baumert C, Hilgeroth A. Recent advances in the development of P-gp inhibitors. Anticancer Agents Med Chem, 2009, 9(4): 415-436.
9.	Fox E, Bates SE. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther, 2007, 7(4): 447-459.
10.	Fang ZY, Chen SD, Chen YS, et al. Pluronic P85 enhances the delivery of phenytoin to the brain versus verapamil in vivo. Latin Am J Pharm, 2014, 33(5): 812-818.
11.	Fang Z, Chen S, Qin J, et al. Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy. Biomaterials, 2016, 97: 110-121.
12.	Brandt C, Bethmann K, Gastens AM, et al. The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis, 2006, 24(1): 202-211.
13.	Volk HA, Arabadzisz D, Fritschy JM, et al. Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. Neurobiol Dis, 2006, 21(3): 633-646.
14.	方子妍, 郭彩凤, 吴逢春, 等. Tariquidar 提高苯妥英钠在颞叶内侧癫痫模型鼠脑中的分布. 临床医学工程, 2017, 24(6): 762-764.
15.	Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972, 32(3): 281-294.
16.	方子妍, 郭彩凤, 吴逢春, 等. 普朗尼克 P85 修饰的苯妥英钠纳米粒对颞叶内侧癫痫大鼠模型的脑靶向作用. 中国神经精神疾病杂志, 2017, 43(6): 356-361.
17.	陈树达, 陈子怡, 方子妍, 等. 普朗尼克 P85 与维拉帕米对苯妥英钠脑靶向分布的比较. 中山大学学报 (医学科学版), 2014, 35(2): 161-168.
18.	Ledwitch KV, Roberts AG. Cardiovascular ion channel inhibitor drug-drug interactions with P-glycoprotein. AAPS J, 2017, 19(2): 409-420.

1. Arroyo S, Brodie MJ, Avanzini G, et al. Is refractory epilepsy preventable? Epilepsia, 2002, 43(4): 437-444.
2. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med, 2000, 342(5): 314-319.
3. Kwan P, Brodie MJ. Definition of refractory epilepsy: defining the indefinable? Lancet Neurol, 2010, 9(1): 27-29.
4. Regesta G, Tanganelli P. Clinical aspects and biological bases of drug-resistant epilepsies. Epilepsy Res, 1999, 34(2-3): 109-122.
5. Luna-Tortos C, Fedrowitz M, Loscher W. Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology, 2008, 55(8): 1364-1375.
6. Luna-Tortos C, Rambeck B, Jurgens UH, et al. The antiepileptic drug topiramate is a substrate for human P-glycoprotein but not multidrug resistance proteins. Pharm Res, 2009, 26(11): 2464-2470.
7. Volk HA, Loscher W. Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures. Brain, 2005, 128(Pt 6): 1358-1368.
8. Baumert C, Hilgeroth A. Recent advances in the development of P-gp inhibitors. Anticancer Agents Med Chem, 2009, 9(4): 415-436.
9. Fox E, Bates SE. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther, 2007, 7(4): 447-459.
10. Fang ZY, Chen SD, Chen YS, et al. Pluronic P85 enhances the delivery of phenytoin to the brain versus verapamil in vivo. Latin Am J Pharm, 2014, 33(5): 812-818.
11. Fang Z, Chen S, Qin J, et al. Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy. Biomaterials, 2016, 97: 110-121.
12. Brandt C, Bethmann K, Gastens AM, et al. The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis, 2006, 24(1): 202-211.
13. Volk HA, Arabadzisz D, Fritschy JM, et al. Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. Neurobiol Dis, 2006, 21(3): 633-646.
14. 方子妍, 郭彩凤, 吴逢春, 等. Tariquidar 提高苯妥英钠在颞叶内侧癫痫模型鼠脑中的分布. 临床医学工程, 2017, 24(6): 762-764.
15. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972, 32(3): 281-294.
16. 方子妍, 郭彩凤, 吴逢春, 等. 普朗尼克 P85 修饰的苯妥英钠纳米粒对颞叶内侧癫痫大鼠模型的脑靶向作用. 中国神经精神疾病杂志, 2017, 43(6): 356-361.
17. 陈树达, 陈子怡, 方子妍, 等. 普朗尼克 P85 与维拉帕米对苯妥英钠脑靶向分布的比较. 中山大学学报 (医学科学版), 2014, 35(2): 161-168.
18. Ledwitch KV, Roberts AG. Cardiovascular ion channel inhibitor drug-drug interactions with P-glycoprotein. AAPS J, 2017, 19(2): 409-420.

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