Pharmacokinetics of perillic acid in humans after a single dose administration of a citrus preparation rich in d-Limonene content

d-Limonene, a monoterpene, is widely distributed as a natural nonnutritive constituent of a variety of foods and volatile oils, particularly citrus oils. d-Limonene and its derived metabolites have been shown to possess cancer chemotherapeutic and chemopreventive efficacy in various preclinical model systems. In our previous work, we have found that lemonade prepared with the whole lemon (Mediterranean-style lemonade) contains high levels of d-limonene. The current study is designed to determine the systemic availability of perillic acid, a major and biologically active metabolite of d-limonene, after a single dose administration of Mediterranean-style lemonade. Healthy individuals were recruited to consume 30-40 oz of Mediterranean-style lemonade with a light breakfast. Blood samples were collected for up to 24 h after the completion of lemonade consumption. d-Limonene levels in the juice and perillic acid levels in plasma were determined by reversed-phase high-performance liquid chromatography with UV detection. It was found that 40 oz of lemonade contained 596 mg of d-limonene and 30 oz contained 447 mg of d-limonene. Plasma concentrations of perillic acid reached maximal levels at 1 h after the lemonade consumption and declined rapidly as a function of time with the terminal elimination half-life ranging from 0.82 to 1.84 h. The maximum plasma perillic acid concentration ranged from 2.08 to 13.98 μM, and the levels were undetectable at 24 h after the lemonade consumption. The area under the plasma concentration-time curves of perillic acid ranged from 5.07 to 32.59 (μM)·h. Our study illustrates that the major metabolite of d-limonene is bioavailable after oral consumption of a citrus preparation rich in d-limonene content.