Alteration of Carvedilol Pharmacokinetics as a Result of Concomitant Administration of Fluoxetine in Human

Objective: The objective of this study is to assess the pharmacokinetics changes of carvedilol when given with a known CYP2D6 inhibitor like fluoxetine. Background: Carvedilol is β-blockers with vasodilating activity, and it is first β-blocker approved by the Food and Drug Administration (FDA) as adjunctive therapy in the treatment of chronic heart failure (CHF). Carvedilol is extensively metabolized in the liver by cytochrome P450 enzymes (CYP2D6 and CYP2C9).Fluoxetine is a selective serotonin reuptake inhibitors, it has an antidepressant effect. When fluoxetine co administered with carvedilol, it may precipitate drug-drug interaction at the site of carvedilol metabolism. Subjects and methods: In a randomized, crossover study in two groups, each contains 6 volunteers. The first group received carvedilol alone firstly, while the second group received carvedilol and fluoxetine firstly. On the day of the study each volunteer in the first group received a single dose of 50 mg carvedilol, the second group of the volunteers received a dose of 20 mg fluoxetine on the night before the study (8 hours before carvedilol administration).Plasma carvedilol was measured up to 8 hours using HPLC. Results:Carvedilol plasma concentration starts to increase rapidly after oral administration to reach maximum concentration (Cmax) 65.5 ± 5.2 ng/ml. whereas, upon co-administration of fluoxetine with carvedilol, the Cmax of carvedilol was increased by 2.21 fold. (145.3 ± 8.5 ng/ml.).The calculated mean AUC0-∞ after the coadministration of carvedilol with fluoxetine was increased by 2.54 fold, (184.88±15.71 ng. hr/ mL.). Also coadministration of carvedilol with fluoxetine results in a significant decrease (P≤0.05) in the calculated mean Cl/F (total body clearance of carvedilol dividing by its bioavailability) (0.11±0.01 L/hr) compared to administration of carvedilol only. A significant decrease (P≤0.05) in the mean calculated volume of distribution of carvedilol divided by its bioavailability (Vd/F) for carvedilol upon co-administration with fluoxetine by 42.2% compared to carvedilol alone. Conclusion: The simultaneous administration of carvedilol with fluoxetine can lead to clinical significant drug-drug interactions, as consequences of changes in pharmacokinetic parameters of carvedilol.