Effects of rutaecarpine on the metabolism and urinary excretion of caffeine in rats

Abstract

Although rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been reported to reduce the systemic exposure of caffeine, the mechanism of this phenomenon is unclear. We investigated the microsomal enzyme activity using hepatic S-9 fraction and the plasma concentration-time profiles and urinary excretion of caffeine and its major metabolites after an oral administration of caffeine in the presence and absence of rutaecarpine in rats. Following oral administration of 80 mg/kg rutaecarpine for three consecutive days, caffeine (20 mg/kg) was given orally. Plasma and urine were collected serially for up to 24 h and the plasma and urine concentrations of caffeine and its metabolites were measured, and compared with those in control rats. The areas under the curve of both caffeine and its three major metabolites (paraxanthine, theophylline, and theobromine) were significantly reduced by rutaecarpine, indicating that caffeine was rapidly converted into the desmethylated metabolites, and that those were also quickly transformed into further metabolites via the hydroxyl metabolites due to the remarkable induction of CYP1A2 and 2E1. The significant induction of ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, and p-nitrophenol hydroxylase strongly supported the decrease in caffeine and its major metabolites in plasma, as well as in urine. These results clearly suggest that rutaecarpine increases the metabolism of caffeine, theophylline, theobromine, and paraxanthine by inducing CYP1A2 and CYP2E1 in rats.

Effects of Rutaecarpine on the Pharmacokinetics of Caffeine and Its Three Metabolites in Rats

“…Furthermore, similar results were obtained in the production of theobromine and theophylline, metabolites produced by CYP2E1. Taken together, the results indicate that production of paraxanthine, theobromine and theophylline from caffeine could also be changed by rutaecarpine, and that the results were very similar with the metabolite production pattern following oral caffeine (Noh et al, 2011).…”

“…The AUC last was 10.67 ± 0.92 μg · hr/ml and the t 1/2(β) was 0.42 ± 0.06 hr, which were 21.0% and 17.6% of control, respectively. In our previous study, oral caffeine showed decrease to 5.2% and 37.0% in the AUC and half-life by rutaecarpine pretreatment, respectively (Noh et al, 2011). In addition, MRT last of caffeine signifi cantly decreased to 26.7% of control by rutaecarpine pretreatment.…”

“…Further metabolism of three demethylated metabolites to others was supported by signifi cant induction of CYP1A2 and CYP2E1 by rutaecarpine (Lee et al, 2004a). Meanwhile, no evidence has been found in the study, regarding possible effects of rutaecarpine on the transporters for caffeine absorption in gastrointestinal tract, and it was postulated that the repeated dose of rutaecarpine might cause the expression of drug transporters in our recent study (Noh et al, 2011).…”

“…Subsequently, therefore, three major metabolites of caffeine were analyzed in rat sera. Three metabolites were analyzed only up to 10 hr in the present study, because our recent study showed rapid production of these metabolites (Noh et al, 2011). Fig.…”

“…Furthermore, caffeine and its three major metabolites have also been used as a tool for studying drug-drug interactions. For example, we recently reported that rutaecarpine might cause signifi cant changes in oral caffeine pharmacokinetics (Noh et al, 2011). In the study, it was found that caffeine was rapidly converted to its three N-demethylated metabolites, which were also quickly transformed to further metabolites, when animals were pretreated with rutaecarpine, a CYP inducer.…”