Transient Inhibition of Cyp3a in Rats by Star Fruit Juice

Abstract

ABSTRACT:Star fruit juice is a potent in vitro inhibitor of CYP3A; however, few reports are available on the inhibition of CYP3A activities by star fruit juice in vivo. Therefore, in this study, we investigated the CYP3A-mediated star fruit-drug interaction in vivo. The effect of star fruit juice on carbamazepine pharmacokinetics was examined in rats. In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.3-fold greater when star fruit juice (2 ml) was orally administered 1 h before the oral administration of carbamazepine (50 mg/kg). In contrast, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the administration of star fruit juice. These results suggest that star fruit juice impairs the function of enteric CYP3A, but not of hepatic CYP3A. In addition, we evaluated the time course of recovery of CYP3A activity that was reduced after the treatment with star fruit juice. The inhibition by star fruit juice was recovered within approximately 24 h. These data suggest that the effect of star fruit juice is mainly reversible and transient. Thus, we discovered that star fruit juice alters the carbamazepine pharmacokinetics in rats.It has been reported that the intake of grapefruit can alter the bioavailability of drugs. Previous studies have shown that coadministration of grapefruit juice with dihydropyridine calcium channel antagonists felodipine and nifedipine resulted in a large increase in the plasma concentration of these drugs, which can cause serious adverse reactions such as headaches, hypotension, facial flushing, and lightheadedness (Bailey et al., 1991;Lundahl et al., 1995). Grapefruit juice interacts with orally administered drugs that undergo substantial presystemic metabolism mediated by CYP3A4 (Bailey et al., 1998). The mechanism of this interaction involves reversible or irreversible (mechanism-based) inhibition of CYP3A4 in the small intestine (Bailey et al., 2000). In addition, recent reports have indicated that various types of fruits, including those of the citrus species, have an inhibitory effect on CYP3A activities in the liver and gut wall and thereby alter the pharmacokinetics of certain drugs (Di Marco et al., 2002;Bailey et al., 2003;Egashira et al., 2004;von Moltke et al., 2004).In a previous study, we attempted to identify fruits that had an inhibitory effect on CYP3A activity. Star fruit was found to be a potent in vitro inhibitor of CYP3A activity; it almost completely inhibits midazolam 1Ј-hydroxylase activity in human liver microsomes (Hidaka et al., 2004). Star fruit has been gaining increasing popularity in Japan, and higher star fruit consumption increases the possibility of star fruit-drug interactions. However, few reports are available on the inhibition of CYP3A activities by star fruit juice in vivo. Hence, it is important to evaluate the CYP3A-mediated drug interactions.In the present study, we conducted an experiment to confirm the CYP3A-med...

Inhibition of Human Liver Cytochrome P450 by Star Fruit Juice

“…Previous studies have suggested that star fruit juice, similar to grapefruit juice, might contain some compounds that are CYP inhibitors (3,4,6). These compounds have not yet been identified.…”

“…In vivo evidence also suggested that star fruit juice inhibited the activity of CYP3A in rats (4). Compared to the control, the area under the concentration-time curve of carbamazepine (a typical CYP3A substrate) increased 1.3-fold following 2 mL star fruit juice administration (4). This indicated that FDI could occur in humans when star fruit juice is co-administered with drugs containing CYP3A substrates.…”

“…Star fruit juice (5.0%, v/v) inhibited midazolam 1'-hydroxylation almost completely (3). In vivo evidence also suggested that star fruit juice inhibited the activity of CYP3A in rats (4). Compared to the control, the area under the concentration-time curve of carbamazepine (a typical CYP3A substrate) increased 1.3-fold following 2 mL star fruit juice administration (4).…”

“…Besides grapefruit juice, juice from other fruits such as banpeiyu (1), pomegranate (2), star fruit (3,4), black berry, and wild grape (5) were also found to inhibit CYP3A in vitro.…”

“…Fruit juice-drug interactions (FDIs) have been a concern since the discovery of the grapefruit juice -drug interaction and much attention has been paid to the inhibitory effects of all kinds of fruit juice towards cytochrome P450 (CYP) (1)(2)(3)(4)(5). Besides grapefruit juice, juice from other fruits such as banpeiyu (1), pomegranate (2), star fruit (3,4), black berry, and wild grape (5) were also found to inhibit CYP3A in vitro.…”