ABSTRACT:In this study, we investigated whether components of pomegranate could inhibit CYP3A-mediated drug metabolism. The ability of pomegranate to inhibit the carbamazepine 10,11-epoxidase activity of CYP3A was examined using human liver microsomes, and pomegranate juice was shown to be a potent inhibitor of human CYP3A. Addition of 25 l (5.0% v/v) of pomegranate juice resulted in almost complete inhibition of the carbamazepine 10,11-epoxidase activity of human CYP3A (1.8%). The inhibition potency of pomegranate juice was similar to that of grapefruit juice. In addition, we investigated the in vivo interaction between pomegranate juice and carbamazepine pharmacokinetics using rats. In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.5-fold higher when pomegranate juice (2 ml) was orally injected 1 h before the oral administration of the carbamazepine (50 mg/kg). On the other hand, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the injection of pomegranate juice. These data suggest that pomegranate juice component(s) impairs the function of enteric but not hepatic CYP3A. Thus, we discovered that a component(s) of pomegranate inhibits the human CYP3A-mediated metabolism of carbamazepine. Furthermore, pomegranate juice alters the carbamazepine pharmacokinetics in rats.

ABSTRACT:There has been very limited information on the capacities of tropical fruits to inhibit human cytochrome P450 3A (CYP3A) activity. Thus, the inhibitory effects of tropical fruits on midazolam 1-hydroxylase activity of CYP3A in human liver microsomes were evaluated. Eight tropical fruits such as common papaw, dragon fruit, kiwi fruit, mango, passion fruit, pomegranate, rambutan, and star fruit were tested. We also examined the inhibition of CYP3A activity by grapefruit (white) and Valencia orange as controls. The juice of star fruit showed the most potent inhibition of CYP3A. The addition of a star fruit juice (5.0%, v/v) resulted in the almost complete inhibition of midazolam 1-hydroxylase activity (residual activity of 0.1%). In the case of grapefruit, the residual activity was 14.7%. The inhibition depended on the amount of fruit juice added to the incubation mixture (0.2-6.0%, v/v). The elongation of the preincubation period of a juice from star fruit (1.25 or 2.5%, v/v) with the microsomal fraction did not alter the CYP3A inhibition, suggesting that the star fruit did not contain a mechanism-based inhibitor. Thus, we discovered filtered extracts of star fruit juice to be inhibitors of human CYP3A activity in vitro.

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...

Kremezin showed potent adsorption capacities for the camptothecin drugs and mitigated the symptoms of diarrhea in rats. These results suggest that Kremezin is useful to prevent the diarrhea in clinical CPT-11 chemotherapy.

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