Evaluation of Brain Pharmacokinetic and Neuropharmacodynamic Attributes of an Antiepileptic Drug, Lacosamide, in Hepatic and Renal Impairment: Preclinical Evidence.
The knowledge of pharmacokinetic and pharmacodynamic properties of antiepileptic drugs is helpful in optimizing drug therapy for epilepsy. This study was designed to evaluate the pharmacokinetic and pharmacodynamic properties of lacosamide in experimentally induced hepatic and renal impairment in seizure animals. Hepatic or renal impairment was induced by injection of carbon tetrachloride or diclofenac sodium, respectively. After induction, the animals were administered a single dose of lacosamide. At different time points, maximal electroshock (MES) seizure recordings were made followed by isolation of plasma and brain samples for drug quantification and pharmacodynamic measurements. Our results showed a significant increase in the area under the curve of lacosamide in hepatic and renal impairment groups. Reduced clearance of lacosamide was observed in animals with renal impairment. Along with pharmacokinetic alterations, the changes in pharmacodynamic effects of lacosamide were also observed in all the groups. Lacosamide showed a significant protection against MES-induced seizures, oxidative stress, and neuroinflammatory cytokines. These findings revealed that experimentally induced hepatic or renal impairment could alter the pharmacokinetic as well as pharmacodynamic properties of lacosamide. Hence, these conditions may affect the safety and efficacy of lacosamide.
Department of Pharmacology, Postgraduate Institute of Medical Education and Research , Chandigarh 160012, India.
Baldeep
0000-0003-2477-7052
B
Kumar
Department of Neurology, Postgraduate Institute of Medical Education and Research , Chandigarh 160012, India.
Manish
M
Modi
Department of Immunopathology, Postgraduate Institute of Medical Education and Research , Chandigarh 160012, India.
Biman
B
Saikia
Department of Pharmacology, Postgraduate Institute of Medical Education and Research , Chandigarh 160012, India.
Bikash
0000-0002-4017-641X
B
Medhi
D000081:Acetamides / Q000097:blood / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002251:Carbon Tetrachloride; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004008:Diclofenac; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D007378:Interleukins / Q000378:metabolism; D000078334:Lacosamide; D008107:Liver Diseases / Q000150:complications / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000150:complications / Q000378:metabolism*; D012640:Seizures / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000081:Acetamides; D000927:Anticonvulsants; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D000078334:Lacosamide; D002251:Carbon Tetrachloride; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9
Lacosamide; Pharmacodynamic; Pharmacokinetic; Renal failure; Seizure