Pomegranate Juice Ellagitannin Metabolites Are Present in Human Plasma and Some Persist in Urine for Up to 48 Hours

Abstract

Ellagitannins (ETs) from pomegranate juice (PJ) are reported to have numerous biological properties, but their absorption and metabolism in humans are poorly understood. To investigate the pharmacokinetics of pomegranate ETs, 18 healthy volunteers were given 180 mL of PJ concentrate, and blood samples were obtained for 6 h afterwards. Twenty-four-hour urine collections were obtained on the day before (-1), the day of (0), and the day after (+1) the study. Ellagic acid (EA) was detected in plasma of all subjects with a maximum concentration of 0.06 +/- 0.01 micromol/L, area under concentration time curve of 0.17 +/- 0.02 (micromol x h) x L(-1), time of maximum concentration of 0.98 +/- 0.06 h, and elimination half-life of 0.71 +/- 0.08 h. EA metabolites, including dimethylellagic acid glucuronide (DMEAG) and hydroxy-6H-benzopyran-6-one derivatives (urolithins), were also detected in plasma and urine in conjugated and free forms. DMEAG was found in the urine obtained from 15 of 18 subjects on d 0, but was not detected on d -1 or +1, demonstrating its potential as a biomarker of intake. Urolithin A-glucuronide was found in urine samples from 11 subjects on d 0 and in the urine from 16 subjects on d +1. Urolithin B-glucuronide was found in the urine of 3 subjects on d 0 and in the urine of 5 subjects on d +1. Urolithins, formed by intestinal bacteria, may contribute to the biological effects of PJ as they may persist in plasma and tissues and account for some of the health benefits noted after chronic PJ consumption. Whether genetic polymorphisms in EA-metabolizing enzymes (e.g., catechol-O-methyl transferase and glucuronosyl transferase) are related to variations in response to PJ remains to be established.

Pomegranate Ellagitannin-Derived Metabolites Inhibit Prostate Cancer Growth and Localize to the Mouse Prostate Gland

“…Therefore, UA was studied in detail, since prior studies demonstrated that UA conjugates were the most prevalent metabolites of EA in human subjects and that they persist for up to 56 h after ingestion of ETs (9,10,12).…”

“…An ET-enriched PE derived from the skin of pomegranate fruit (Punica granatum L., Wonderful Variety, Paramount Farms, Lost Hills, CA), was standardized to 37% ETs (as punicalagin isomers) and 3.5% free EA as reported (15). PE was administered to animals in doses based on the amount of ETs (as punicalagins) in a single serving of PJ (240 mL of single strength juice, ∼80 mg of ETs) (9). The equivalent dose that would be administered to a 70 kg human was calculated for a mouse of 25 g body weight to be 0.03 mg of ETs.…”

“…In fact, urolithins appear in blood, urine, and feces of human volunteers 12-24 h after consumption of a single dose of several ET-rich foods and persist in vivo for up to 48-56 h after ingestion (9)(10)(11)(12). Despite these advances in understanding ET metabolism in rodents (13,14) and humans (9-12), there have been no studies determining the disposition of ET metabolites to tissues of interest including the prostate.…”

Urolithin B, a newly identified regulator of skeletal muscle mass

“…The first product of ellagic acid catabolism is urolithin D, and successive loss of hydroxy groups result in the formation of urolithins C, A, and B 3. All mammals seem able to produce urolithins from ellagitannins found in food 4, 5. In healthy humans, urolithins A and B are most abundant 5, 6.…”

“…All mammals seem able to produce urolithins from ellagitannins found in food 4, 5. In healthy humans, urolithins A and B are most abundant 5, 6. Urolithin A is the most reported analogue due to its anti‐oxidative and anti‐inflammatory properties in various tissues 7, 8, 9, 10.…”