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Pharmazie. 2009 Aug;64(8):525-31.

Influence of grapefruit juice on the pharmacokinetics of diltiazem in Wistar rats upon single and multiple dosage regimens.

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  • 1Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.


Drug efflux by intestinal P-glycoprotein (P-gp) is recognized as a significant biochemical barrier affecting oral absorption for a number of drugs apart from the cytochrome P450 3A enzyme. Various conflicting reports have been published regarding the effects of grapefruit juice (GFJ) on P-gp mediated drug efflux, in which GFJ has been shown to have no effect, as an inhibitor effect or activation of the enzyme. Therefore the present study's objective was to provide clarification of previous findings, adopting a two-way approach, involving both single dose and multiple dosage regimens. Diltiazem (DTZ) 15 mg/kg was administered concomitantly with 5 ml/kg of GFJ to one group (n = 6) of male Wistar rats and another group (n = 6) of animals were provided distilled water with DTZ (the control). A third group of rats was administered GFJ orally for six days and on seventh day GFJ and DTZ were administered concomitantly. The Cmax and AUC of DTZ were decreased significantly in the presence of multiple dose treatment of GFJ. These data were also decreased in presence of simultaneous treatment of single dose GFJ. In vitro metabolism studies and gut sac experiments were conducted in order to understand the mechanism involved. In the liver S9 fraction prepared from the rats treated with multiple doses of GFJ, DTZ metabolism was significantly increased compared to the control. Furthermore, the amount of drug transported from the duodenum was reduced in GFJ treated rats compared to that of the control (1581.0 +/- 7.8 nM vs 1084.81 +/- 6.1 nM, respectively). Grapefruit juice was also reported to inhibit the organic anion transporting polypeptide (OATP), an influx transporter thus reducing the blood levels of OATP substrates which was evident from the in vitro studies. The amount of drug transported from the duodenum was reduced in the presence of pravastatin, a specific OATP inhibitor (1581.0 +/- 7.8 nM to 1265.0 +/- 5.5 nM). Oral single dose exposure to GFJ showed no effect on P-gp, whereas multiple dose administration of GFJ resulted in increased levels of P-gp expression and decreased levels of OATP, thus showing a varied effect on intestinal absorption, and therefore overcoming the inhibition of DTZ metabolism in rats.

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