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Drug Metabolism and Disposition Fast Forward
First published on January 26, 2005; DOI: 10.1124/dmd.104.002824

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Received for publication November 3, 2004.
Revised January 20, 2005.
Accepted for publication January 24, 2005.

EFFECTS OF POMEGRANATE JUICE ON HUMAN CYTOCHROME P450 3A (CYP3A) AND CARBAMAZEPINE PHARMACOKINETICS IN RATS

Muneaki Hidaka 1*, Manabu Okumura 1, Ken-ichi Fujita 1, Tetsuya Ogikubo 1, Keishi Yamasaki 1, Tomomi Iwakiri 1, Nao Setoguchi 1, Kazuhiko Arimori 1

1 Miyazaki Medical College Hospital

* Address correspondence to: E-mail: yshidaka{at}med.miyazaki-u.ac.jp

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 µl (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 prior to 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 component(s) of pomegranate inhibits the human CYP3A-mediated metabolism of carbamazepine. Further, pomegranate juice alters the carbamazepine pharmacokinetics in rats.


Key words: CYP3A, drug interactions, first-pass metabolism, human CYP enzymes


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