Effect of Amitriptyline on the Pharmacokinetics of Divalproex Sodium in Normal Rabbits
The present study was aimed at investigating the effect of Amitriptyline on the pharmacokinetic of Divalproex in rabbits. Divalproex and Amitriptyline are used for long duration and indicated for CNS disorder like depressive disorder, personality disorder and migraine, respectively. The pharmacokinetic parameters of Divalproex sodium (6 mg/kg, p.o.) was compared with concomitant administration of Divalproex sodium (6 mg/kg, p.o.) and Amitriptyline (10 mg/kg, p.o.). The blood samples were collected at different time interval of 30 min, 1st, 2nd, 4th, 8th, and 16th hour. Divalproex dissociates to release valproate and valproic acid in the gastrointestinal tract. The concentration of Valproic acid (VPA) in serum was then estimated by HPLC coupled with Mass Spectroscpoy (LC-MS/MS). The serum concentration of VPA was significantly increased after Amitriptyline treatment for 7 days. Pharmacokietic parameters like AUC, AUMC, T1/2 and Cmax of VPA showed significant change after Amitriptyline treatment in healthy albino rabbits. Divalproex and Amitriptyline both are metabolized by the same enzyme; CYP2C9. Amitriptyline inhibits UDP-glucuronosyltransferases (UTG), where Divalproex is substrate of UTG metabolism. Both reasons may lead to increase in serum VPA concentration. Change in the time and frequency of administration of Divalproex sodium is suggested when both drugs are administered concomitantly. Therapeutic drug monitoring should be performed as combination may lead to remarkable increase in valproic acid serum level.