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First published on March 28, 2007; DOI: 10.1124/dmd.106.013268

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Received for publication October 16, 2006.
Revised March 23, 2007.
Accepted for publication March 23, 2007.

ESTERASE INHIBITION ATTRIBUTE OF GRAPEFRUIT JUICE LEADING TO A NEW DRUG INTERACTION

Ping Li 1*, Patrick S. Callery 2, Liang-Shang Gan 3, Suresh K. Balani 4

1 Millennium Pharmaceuticals Inc. 2 West Virginia University 3 Millennium Pharmaceuticals Inc. 4 Millennium Pharmaceuticals, Inc.

* Address correspondence to: E-mail: ping.li{at}biogenidec.com

Abstract

This report describes a newly identified potential of grapefruit juice (GFJ) in mediating pharmacokinetic drug interactions due to its capability of esterase inhibition. The study demonstrates that GFJ inhibits purified porcine esterase activity towards p-nitrophenylacetate and the prodrugs lovastatin and enalapril. In rat and human hepatic or gut S9 fractions and rat gut lumen GFJ inhibited the hydrolysis of enalapril and lovastatin, which are known to be metabolized principally by esterases, with lovastatin metabolized also by CYP3A. In Caco-2 cells, with minimal CYP3A activity, permeability of these prodrugs was increased in the presence of GFJ. In rats, oral coadministration of GFJ or an esterase inhibitor bis-(p-nitrophenylphosphate) with the prodrugs led to respective increases in plasma AUC by 70% or 57% for enalaprilat and 279% or 141% for lovastatin acid. Additionally, portal vein cannulated rats pretreated with GFJ at -15 and -2 hr prior to lovastatin administration (10 mg/kg PO) as a solution (a) in water showed 49% increase (CYP3A inhibited), and (b) in GFJ showed 116% increase (both CYP3A and gut esterase inhibited) in the portal plasma exposure to the active acid, compared to a non-GFJ pretreatment group. Overall, along with the CYP3A inactivation by GFJ, the decreased esterase activity also played a significant role in increasing the metabolic stability and permeability of esters leading to enhancement of exposure to the active drugs in rats. These new esterase inhibition findings indicate that the potential of drug interaction between ester prodrugs and GFJ should also be considered in the clinic.


Key words: drug interactions, first-pass metabolism, inhibition, oral absorption, prodrugs


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Home page
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P. Li, P. S. Callery, L.-S. Gan, and S. K. Balani
Esterase Inhibition by Grapefruit Juice Flavonoids Leading to a New Drug Interaction
Drug Metab. Dispos., July 1, 2007; 35(7): 1203 - 1208.
[Abstract] [Full Text] [PDF]


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