Esterase Inhibition Attribute of Grapefruit Juice Leading to a New Drug Interaction

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 ac-etate 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 me-tabolized principally by esterases, lovastatin being metabolized also by CYP3A. In Caco-2 cells, with minimal CYP3A activity, per-meability 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 befor