RT Journal Article
SR Electronic
T1 Esterase Inhibition Attribute of Grapefruit Juice Leading to a New Drug Interaction
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1023
OP 1031
DO 10.1124/dmd.106.013268
VO 35
IS 7
A1 Ping Li
A1 Patrick S. Callery
A1 Liang-Shang Gan
A1 Suresh K. Balani
YR 2007
UL http://dmd.aspetjournals.org/content/35/7/1023.abstract
AB This report describes a newly identified potential of grapefruit juice (GFJ) in mediating pharmacokinetic drug interactions due to its capability to inhibit esterase. The study demonstrates that GFJ inhibits purified porcine esterase activity toward p-nitrophenyl acetate 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, lovastatin being 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 area under the curve by 70% or 57% for enalaprilat and 279% or 141% for lovastatin acid. In addition, portal vein-cannulated rats pretreated with GFJ at –15 and –2 h before lovastatin administration (10 mg/kg p.o.) as a solution, 1) in water and 2) in GFJ, showed, respectively, a 49% increase (CYP3A-inhibited) and a 116% increase (both CYP3A and gut esterase-inhibited) in the portal plasma exposure to the active acid, compared with 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. The American Society for Pharmacology and Experimental Therapeutics