Pomegranate compound with anti-aging effects passes human trial

He is talking about the bioavailability of exogenously supplemented ellagic acid, not its ability to be converted in-vitro in a controlled study. Its bioavailability has been questioned in the past, but those studies may not have gotten the whole picture. It's complicated.

https://www.sciencedirect.com/science/article/pii/S1756464615004363

Ellagic acid (EA) is a polyphenol that must be released from the non-bioavailable ellagitannins in pomegranates, walnuts or strawberries to be absorbed. To estimate whether EA bioavailability could be improved after consumption of a high free EA amount, we conducted a crossover pharmacokinetic study in healthy volunteers that consumed two pomegranate extracts providing either 130 mg punicalagin+524 mg EA (PE-1) or 279 mg punicalagin+25 mg EA (PE-2).

We report here for the first time that the intake of a high free EA dose does not enhance EA bioavailability. In addition, a large interindividual variability was observed. The results obtained in the crossover human study were supported by the in vitro gastrointestinal digestion that identified the high influence of pH and protein content on the solubility and further availability of EA and punicalagin.

The plasma EA pharmacokinetic parameters described in our study (Table 1) are in agreement with those previously reported (Mertens-Talcott et al, 2006, Seeram et al, 2004, Seeram et al, 2006, Seeram et al, 2008, Stoner et al, 2005). In these studies, the intake of ETs, mainly punicalagin, approximately ranged from 300 to 400 mg, and free EA ranged from 12 to 25 mg. These figures were close to those provided by the ‘conventional’ extract PE-2 in the present study. The intake of 4 capsules of PE-2 provided a total amount of 9.7 mg punicalin, 279 mg punicalagin and 50.4 mg EA derivatives (including 25 mg free EA). In the case of PE-1, the total amount ingested was 3.6 mg punicalin, 129.6 mg punicalagin and 529 mg of EA derivatives (including 524 mg free EA). Results showed that the intake of a 21-fold higher dose of free EA provided by PE-1 did not significantly change plasma EA values (Table 1). In addition, it seems that individuals' BMI does not affect EA bioavailability since similar pharmacokinetic values were found in either obese (Mertens-Talcott et al., 2006) or normoweight participants (Seeram et al, 2006, Seeram et al, 2008; present study).

Interestingly, we found a large inter-individual variability in both the amount of EA absorbed and the pharmacokinetic profile. Indeed, some volunteers showed peaks of absorption over 5 hours or even at 24 hours. Both the high individual variability and unexpected Cmax values after 24 h were also described by Mertens-Talcott et al. (2006). These authors eliminated these values (three subjects from eleven who completed the study) as non-compliance was assumed. However, we believe that this behaviour is inherent to the limited EA bioavailability and could be related to its pH-dependent solubility.

So there are some issues with EA bioavailability. Then you have the big issue of ellagic acid's insolubility at low pH, which is what it would be in your stomach.

It is known that EA is highly insoluble in aqueous media, especially at acid pH, where most EA is not ionised (Bala et al, 2006, Hasegawa et al, 2003). This low solubility is partly due to its high degree of crystallinity, which is directly related to its planar and symmetrical structure and the hydrogen-bonding network formed in the crystal (Li, Harich, Wegiel, Taylor, & Edgara, 2013). Indeed, previous animal studies identified the low solubility of EA in aqueous media as a major drawback in EA absorption (Daniel, Ratnayake, Kinstle, & Stoner, 1991) as well as its ability to bind the intestinal epithelium (Whitley, Sweet, & Walle, 2006). In the present study, we confirmed the very low recovery of free EA under in vitro gastric conditions, i.e. the more free EA (PE-1) the lower amount of soluble EA was detected (Table 2). However, in the pancreatic phase of the in vitro digestion, the solubility EA greatly increased because of the deprotonation at hydroxyl group positions under mild alkaline conditions (Bala et al., 2006). This increase in the solubility could promote the absorption at intestinal level, which could explain the detection of EA in plasma at long post-ingestion times (5 or even 24 h). However, although EA solubility greatly increased at pH over 7.5, this did not match in the human study where higher EA absorption at longer post-ingestion times was only observed in a few cases, especially after the intake of PE-1. This supported the idea that EA intestinal absorption was hampered and/or saturated, which was in agreement with preclinical studies where EA showed a limited transcellular transport (Whitley, Sweet, & Walle, 2006). In addition, this saturation phenomenon is also sustained by in vitro studies that have also reported the efficient EA transport by intestinal organic anion transporters (OATs) with a very high affinity for hOAT1 (Whitley, Sweet, & Walle, 2005), which resulted inhibited at EA concentrations (5–25 µM) that can be reached in the human colonic mucosa (Núñez-Sánchez et al., 2014).

This in vivo–in vitro study identifies that the human EA bioavailability shows a large interindividual variability, mainly due to a number of key factors: i) low solubility of free EA under gastric conditions; ii) type of ET as EA precursor; and iii) limited intestinal EA absorption. In addition, as only circulating free EA was detected, a low affinity of phase-II enzymes for EA is suggested. Free EA concentrations rarely exceed 100 nM in human plasma even upon a high free EA intake. Nevertheless, the bioavailability of EA, as the unchanged fraction that reaches the systemic circulation, is not as low as previously thought. This could be useful to design in vitro experiments to unravel possible EA-mediated mechanisms using physiologically relevant EA concentrations in endothelial cells or cells from distant organs (lungs, prostate, etc.). A higher free EA intake does not enhance EA bioavailability, but the biological action in the gastrointestinal tract could be higher and also promotes the production of urolithins, which could critically contribute to the final health benefits. A search for specific formulations with optimised ETs–EA ratios to maximise EA and Uros-derived effects is warranted.