EFFECTS OF DIVALPROEX SODIUM ON AMITRIPTYLINE AND NORTRIPTYLINE PHARMACOKINETICS

Background: Divalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phas e of bipolar syndrome. Because amitriptyline is also prescribed in the se patient populations, data are needed on their potential for interac tion. Methods: The effect of concomitant administration of divalproex sodium on the pharmacokinetics of amitriptyline and its active metabol ite, nortriptyline, was investigated in an open-label, sequential, two -period phase I study. Ten healthy male and five healthy female subjec ts received 50 mg amitriptyline hydrochloride on two occasions: (1) al one (period 1) and (2) 2 hours after receiving the ninth dose of 500 m g divalproex sodium (Depakote) administered once every 12 hours (perio d 2). Results: Amitriptyline area under the curve was increased 31% fr om the combined effect of decreased firs-pass metabolism and inhibitio n of systemic metabolism. The elevated nortriptyline plasma levels ref lected primarily the increase in amitriptyline concentrations but also appeared to involve modest inhibition of nortriptyline elimination. F or the sum of amitriptyline and nortriptyline concentrations, the peak plasma concentration mean was 19% higher with concomitant divalproex dosing. The mean area under the curve for the sum of amitriptyline and nortriptyline concentrations was 42% higher with concomitant divalpro ex dosing than it was for dosing with amitriptyline alone. Conclusion: These results suggested that a lower dose of amitriptyline might be c onsidered when divalproex is administered concomitantly.