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Phase I and Phase II Human Clinical Trials / Human Translational Research

Pharmacokinetics and dose response

Abstract Examples

Unlu NZ, Bohn T, Francis DM, Clinton SK, Schwartz SJ. Carotenoid absorption in humans consuming tomato sauces obtained from tangerine or high-beta-carotene varieties of tomatoes. J Agric Food Chem 2007.

Tomato sauces were produced from unique tomato varieties to study carotenoid absorption in humans. Tangerine tomatoes, high in cis-lycopene, especially prolycopene (7Z,9Z,7'Z,9'Z), and high-beta-carotene tomatoes as an alternative dietary source of beta-carotene were grown and processed. Sauces were served after 2 week washout periods and overnight fasting for breakfast to healthy subjects (n = 12, 6M/6F) in a randomized crossover design. The serving size was 150 g (containing 15 g of corn oil), tangerine sauce containing 13 mg of lycopene (97.0% as cis-isomers) and high-beta-carotene sauce containing 17 mg of total beta-carotene (1.6% as the 9-cis-isomer) and 4 mg of lycopene. Blood samples were collected 0, 2, 3, 4, 5, 6, 8, and 9.5 h following test meal consumption and carotenoids determined in the plasma triacylglycerol-rich lipoprotein fraction by HPLC-electrochemical detection. Baseline-corrected areas under the concentration vs time curves (AUC) were used as a measure of absorption. AUC0-9.5h values for total lycopene in the tangerine sauce group were 870 +/- 187 (nmol.h)/L (mean +/- SEM) with >99% as cis-isomers (59% as the tetra-cis-isomer). The AUC0-9.5h values for total beta-carotene and lycopene after consumption of the high-beta-carotene sauce were 304 +/- 54 (4% as 9-cis-carotene) and 118 +/- 24 (nmol.h)/L, respectively. Lycopene dose-adjusted triacylglycerol-rich lipoprotein AUC responses in the tangerine sauce group were relatively high when compared to those in the literature and the high-beta-carotene group. The results support the hypothesis that lycopene cis-isomers are highly bioavailable and suggest that special tomato varieties can be utilized to increase both the intake and bioavailability of health-beneficial carotenoids.

Walsh KR, Haak SJ, Bohn T, Tian Q, Schwartz SJ, Failla ML. Isoflavonoid glucosides are deconjugated and absorbed in the small intestine of human subjects with ileostomies. Am J Clin Nutr 2007.

Although soy isoflavonoids have a number of health-promoting benefits, information concerning the sites of their absorption and metabolism in humans remains limited. Isoflavonoid absorption from the gut requires deconjugation of glucosides to aglycones. The objective was to investigate the role of the small intestine in isoflavonoid absorption and metabolism in humans. Human subjects with fully functional gastrointestinal tracts (n = 6) and ileostomy subjects (n = 6) were fed a single soy meat containing 64.8 mg isoflavonoid aglycone equivalents (95% as glucosides). Metabolism of isoflavonoids in the upper gastrointestinal tract was examined by analyzing ileal effluent from ileostomy subjects, and absorption was assessed indirectly by quantifying isoflavonoids and several metabolites in 24-h urine pools. Chyme contained 36.7% of ingested isoflavonoid aglycone equivalents, primarily (95.8%) as aglycones. Qualitative profiles ((x) over bar +/- SEM) of isoflavonoid excretion in urine (daidzein > glycitein > genistein) and the quantity of isoflavonoid equivalents were not significantly different between the control (18.4 +/- 2.2 mg) and ileostomy (13.5 +/- 3.2 mg) subjects. Dihydrodaidzein was present in the urine of all subjects, although the amount excreted by ileostomy subjects was less than that excreted by the control subjects. The percentage of producers and mean quantities of dihydrogenistein, equol, and O-desmethylangolensin in the urine of ileostomy subjects also were lower than those of control subjects. Ileostomy subjects efficiently deglycosylate isoflavonoid glucosides in the small intestine and appear to absorb aglycones with an efficiency comparable with that of control subjects. However, the production of microbial metabolites of isoflavonoids is limited in ileostomy subjects.

Tian Q, Giusti MM, Stoner GD, Schwartz SJ. Urinary excretion of black raspberry (Rubus occidentalis) anthocyanins and their metabolites. J Agric Food Chem 2006.

Anthocyanins are the most abundant phenolic compounds, widely distributed in fruits and vegetables, and exhibit potent antioxidant capacity. Humans ingest a significant amount of anthocyanins in the daily diet. The objective of the current study was to examine human absorption and metabolism of black raspberry anthocyanins when administered at high doses (2.69 +/- 0.085 g/day). Ten healthy men consumed 45 g of freeze-dried black raspberries daily for 1 week. Urine samples were collected over a 12 h period in 4 h intervals at day 1 and day 7. Urinary anthocyanins were analyzed by high-performance liquid chromatography coupled to a photodiode array detector and a tandem mass spectrometer using precursor ion and product ion analyses. Anthocyanins were excreted in intact forms and metabolized into methylated derivatives in human urine. The urinary excretion of anthocyanins reached a maximum concentration (1091.8 +/- 1081.3 pmol/L, n = 10) during the 4-8 h period after black raspberry ingestion. As compared to the anthocyanin distribution in black raspberries, urinary cyanidin 3-xylosylrutinoside was detected at a higher concentration than that of cyanidin-3-rutinoside.