Bupropion Increased More than Five Times the Systemic Exposure to Aripiprazole: An In Vivo Study in Wistar albino Rats.

Background/Objectives: In psychiatric disorders, antipsychotics and antidepressant medication are often administered together. Aripiprazole, a third-generation antipsychotic drug, is extensively metabolized by CYP2D6 and CYP3A4 isoenzymes, while bupropion, used in depressive disorders, is known as a moderate or strong CYP2D6 enzyme inhibitor. This in vivo experiment aimed to assess the presence of a pharmacokinetic drug interaction between aripiprazole and bupropion and its magnitude on the systemic exposure of aripiprazole. Methods: 24 healthy Wistar albino male rats were included in two study groups. A single dose of 8 mg/kg aripiprazole was given to rats in the reference group, while the test group received repeated doses of bupropion for 6 days, followed by a single dose of aripiprazole. An LC-MS/MS method was developed for the concomitant quantification of aripiprazole and its active metabolite, dehydroaripiprazole, and non-compartmental analysis was employed to assess their pharmacokinetic parameters. Results: The mean AUC_0-∞ of aripiprazole increased 5.65-fold (1117.34 ± 931.41 vs. 6311.66 ± 2978.71 hr·ng/mL), the mean C_max increased by 96.76% and the apparent systemic clearance decreased over 9-fold after bupropion repeated doses. The exposure to aripiprazole's active metabolite increased as well, having a 4-fold increase in the mean AUC_0-∞ (from 461.13 ± 339.82 to 1878.66 ± 1446.91 hr·ng/mL) and a 2-fold increase in the mean C_max. Conclusions: The total exposure to the aripiprazole parent compound and active moiety significantly increased after bupropion pretreatment in this preclinical in vivo experiment. Clinical studies should further establish the significance of this interaction in humans.