Influence of Fluvoxamine on Carvedilol Metabolism and Plasma Disposition – in vitro and in vivo Experiments

Carvedilol is one of the most used cardiovascular drugs, highly metabolized by CYP450 2D6, 1A2, 2C9. Fluvoxamine, an antidepressant agent, is a moderate/potent inhibitor of these enzymes. There is the risk of drug-drug interaction when these two drugs are concomitantly administered. The aim of this study was to investigate the drug-drug interactions between carvedilol and fluvoxamine in vitro and in rats.

There were two periods: reference and test. In the first period each rat received an oral dose of 3.57 mg/kg body weight [b.w.] carvedilol.  In the test period, carvedilol was administered after a pre-treatment with multiple oral doses of fluvoxamine (14.28 mg/kg b.w.). HPLC-MS was the device used to determine the plasma concentration of carvedilol. The PK parameters were calculated by non-compartmental analysis. Rat liver microsomal incubation systems were used to investigate the effect of fluvoxamine on the metabolic rate of carvedilol.

Fluvoxamine co-administered with carvedilol can change the PK parameters (increase AUC, t_1/2, decrease the Cl). In vitro experiment showed that fluvoxamine decreased the metabolic rate of carvedilol.

The present study demonstrated the pharmacokinetic drug-drug interaction between carvedilol and fluvoxamine in vitro and in vivo. Fluvoxamine significantly influenced the pharmacokinetic of carvedilol, due to its capacity of CYP2D6 and CYP1A2 inhibition. As a result of this interaction the exposure to carvedilol was significantly increased. This is the reason why co-administration of carvedilol and fluvoxamine needs precaution.