Date of Graduation
School of Medicine
Physiology, Pharmacology & Neuroscience
Patrick S. Callery.
Grapefruit juice (GFJ) is well known to be a potent inhibitor of the CYP3A enzyme leading to drug-drug interactions. This study describes a newly identified potential of GFJ in mediating pharmacokinetic drug-drug interactions due to its capability of esterase inhibition. The study demonstrates that GFJ inhibits purified porcine esterase activity towards para-nitrophenylacetate (PNPA) 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, 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 for enalaprilat for lovastatin acid. Studies in portal vein cannulated rats demonstrated that in addition to CYP3A inactivation, GFJ also played a significant role in the decreased esterase activity leading to enhancement of exposure to the active drugs in rats.;To identify the GFJ components responsible for this new GFJ-prodrug interaction, the esterase inhibitory potential of ten constituitive flavonoids and furanocoumarins was investigated. The furanocoumarins bergamottin, 6',7'-dihydroxybergamottin and bergapten and the glycosidic flavonoids naringin and hesperidin, at concentrations found in GFJ or higher did not inhibit the hydrolysis of PNPA by purified porcine esterase and human liver microsomes. However, the flavonoid aglycones morin, galangin, kaempferol, quercetin, and naringenin showed appreciable inhibition of PNPA hydrolysis. In Caco-2 cells, the permeability coefficient of prodrug lovastatin and enalapril was increased in the presence of the active flavonoids kaempferol and naringenin, consistent with inhibition of esterase activity. In rats, oral coadministration of kaempferol and naringenin with these prodrugs led to significant increases in plasma exposure to the active acids. Overall, a series of flavonoids present in GFJ are identified as carboxylesterase inhibitors, of which kaempferol, and naringenin are shown to mediate pharmacokinetic drug interaction with prodrugs lovastatin and enalapril due to their ability to inhibit esterase.
Li, Ping, "Esterase inhibition by grapefruit juice and its components leads to newly identified drug interactions" (2006). Graduate Theses, Dissertations, and Problem Reports. 2446.