Bioavailability Studies - TOCOTRIENOL Tocotrienol.org

Human Studies/ Cohort Studies
Article	Study objective/ findings
Alpha-tocotrienol is the most abundant tocotrienol isomer circulated in plasma and lipoproteins after postprandial tocotrienol-rich vitamin E supplementation Fairus, S., et.al (2012). Nutr J.	T3 are detected in circulating human plasma and lipoproteins, although at concentrations significantly lower than α-tocopherol (α-T). T3, especially α-T3 is known to be neuropotective at nanomolar concentrations and this study evaluated the postprandial fate of T3 and α-T in plasma and lipoproteins. Bio-discrimination between vitamin E isomers in humans reduces the rate of T3 absorption and affects their incorporation into lipoproteins. Although low absorption of T3 into circulation may impact some of their physiological functions in humans, T3 have biological functions well below concentration noted in this study.
Influence of lipolysis and droplet size on tocotrienol absorption from self-emulsifying formulations. Yap, S.P., et.al (2004). Int J Pharm.	A single dose comparative bioavailability study was conducted to evaluate the bioavailability of tocotrienols from two self-emulsifying formulations, one of which produced an emulsion that readily lipolysed under in vitro condition (SES-A), while the other produced a finer dispersion with negligible lipolysis (SES-B) in comparison with that of a non-self-emulsifying formulation in soya oil. The study was conducted according to a three-way crossover design using six healthy human volunteers. Statistically significant differences were observed between the logarithmic transformed peak plasma concentration (Cmax) and total area under the plasma concentration-time curve (AUC(0-infinity)) values of both SES-A and -B compared to NSES-C indicating that SES-A and -B achieved a higher extent of absorption compared to NSES-C. Moreover, the 90% confidence interval of the AUC(0-infinity) values of both SES-A and -B over those of NSES-C were between 2-3 suggesting an increase in bioavailability of about two-three times compared to NSES-C. Both SES-A and -B also achieved a faster onset of absorption. However, both SES-A and -B had comparable bioavailability, despite the fact that SES-B was able to form emulsions with smaller droplet size. Thus, it appeared that both droplet sizes as well as the rate and extent of lipolysis of the emulsion products formed were important for enhancing the bioavailability of the tocotrienols from the self-emulsifying systems.
Pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienol Yap, S.P., et.al (2001). J Pharm Pharmacol.	The pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under fed and fasted conditions in eight healthy volunteers were investigated. The volunteers were administered a single oral dose of mixed tocotrienols (300 mg) under fed or fasted conditions. The bioavailability of tocotrienols under the two conditions was compared using the parameters peak plasma concentration (Cmax), time to reach peak plasma concentration (Tmax) and total area under the plasma concentration-time curve (AUC(o-infinity)). A statistically significant difference was observed between the fed and fasted logarithmic transformed values of Cmax (P < 0.01) and AUC(0-infinity) (P < 0.01) for all three tocotrienols. In addition, the 90% confidence intervals for the ratio of the logarithmic transformed AUC(0-infinity) values of alpha-, gamma- and delta-tocotrienols under the fed state over those of the fasted state were found to lie between 2.24-3.40, 2.05-4.09 and 1.59-3.81, respectively, while those of the Cmax were between 2.28-4.39, 2.31-5.87 and 1.52-4.05, respectively. However, no statistically significant difference was observed between the fed and fasted Tmax values of the three homologues. The mean apparent elimination half-life (t(1/2)) of alpha-, gamma- and delta-tocotrienols was estimated to be 4.4, 4.3 and 2.3 h, respectively, being between 4.5- to 8.7-fold shorter than that reported for alpha-tocopherol. No statistically significant difference was observed between the fed and fasted t(1/2) values. The mean apparent volume of distribution (Vd/f) values under the fed state were significantly smaller than those of the fasted state, which could be attributed to increased absorption of the tocotrienols in the fed state.
Alpha- and gamma-tocotrienols are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine. Lodge, J.K., et.al (2001). Lipids.	Limited information is available regarding metabolism of vitamin E forms, especially the tocotrienols. Carboxyethyl-hydroxychromans (alpha- and gamma-CEHC) are human urinary metabolites of alpha- and gamma-tocopherols, respectively. To evaluate whether tocotrienols are also metabolized and excreted as urinary CEHC, urine was monitored following tocotrienol supplementation. Complete (24 h) urine collections were obtained for 2 d prior to (baseline), the day of, and 2 d after human subjects (n = 6) ingested tocotrienol supplements. The subjects consumed 125 mg gamma-tocotrienyl acetate the first week, then the next week 500 mg; then 125 mg alpha-tocotrienyl acetate was administered the third week, followed by 500 mg the fourth week. Urinary alpha- and gamma-CEHC were measured by high-performance liquid chromatography with electrochemical detection. Urinary gamma-CEHC levels rose about four- to sixfold in response to the two doses of gamma-tocotrienol and then returned to baseline the following day. Significant (P < 0.0001) increases in urinary alpha-CEHC were observed only following ingestion of 500 mg alpha-tocotrienyl acetate. Typically, 1-2% of alpha-tocotrienyl acetates or 4-6% of gamma-tocotrienyl acetates were recovered as their respective urinary CEHC metabolites. A gamma-CEHC excretion time course showed an increase in urinary gamma-CEHC at 6 h and a peak at 9 h following ingestion of 125 mg gamma-tocotrienyl acetate. In summary, tocotrienols, like tocopherols, are metabolized to CEHC; however, the quantities excreted in human urine are small in relation to dose size.

Human Studies/ Cohort Studies

Article

Study objective/ findings

Alpha-tocotrienol is the most abundant tocotrienol isomer circulated in plasma and lipoproteins after postprandial tocotrienol-rich vitamin E supplementation

Fairus, S., et.al (2012). Nutr J.

T3 are detected in circulating human plasma and lipoproteins, although at concentrations significantly lower than α-tocopherol (α-T). T3, especially α-T3 is known to be neuropotective at nanomolar concentrations and this study evaluated the postprandial fate of T3 and α-T in plasma and lipoproteins. Bio-discrimination between vitamin E isomers in humans reduces the rate of T3 absorption and affects their incorporation into lipoproteins. Although low absorption of T3 into circulation may impact some of their physiological functions in humans, T3 have biological functions well below concentration noted in this study.

Influence of lipolysis and droplet size on tocotrienol absorption from self-emulsifying formulations.

Yap, S.P., et.al (2004). Int J Pharm.

A single dose comparative bioavailability study was conducted to evaluate the bioavailability of tocotrienols from two self-emulsifying formulations, one of which produced an emulsion that readily lipolysed under in vitro condition (SES-A), while the other produced a finer dispersion with negligible lipolysis (SES-B) in comparison with that of a non-self-emulsifying formulation in soya oil. The study was conducted according to a three-way crossover design using six healthy human volunteers. Statistically significant differences were observed between the logarithmic transformed peak plasma concentration (Cmax) and total area under the plasma concentration-time curve (AUC(0-infinity)) values of both SES-A and -B compared to NSES-C indicating that SES-A and -B achieved a higher extent of absorption compared to NSES-C. Moreover, the 90% confidence interval of the AUC(0-infinity) values of both SES-A and -B over those of NSES-C were between 2-3 suggesting an increase in bioavailability of about two-three times compared to NSES-C. Both SES-A and -B also achieved a faster onset of absorption. However, both SES-A and -B had comparable bioavailability, despite the fact that SES-B was able to form emulsions with smaller droplet size. Thus, it appeared that both droplet sizes as well as the rate and extent of lipolysis of the emulsion products formed were important for enhancing the bioavailability of the tocotrienols from the self-emulsifying systems.

Pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienol

Yap, S.P., et.al (2001). J Pharm Pharmacol.

The pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under fed and fasted conditions in eight healthy volunteers were investigated. The volunteers were administered a single oral dose of mixed tocotrienols (300 mg) under fed or fasted conditions. The bioavailability of tocotrienols under the two conditions was compared using the parameters peak plasma concentration (Cmax), time to reach peak plasma concentration (Tmax) and total area under the plasma concentration-time curve (AUC(o-infinity)). A statistically significant difference was observed between the fed and fasted logarithmic transformed values of Cmax (P < 0.01) and AUC(0-infinity) (P < 0.01) for all three tocotrienols. In addition, the 90% confidence intervals for the ratio of the logarithmic transformed AUC(0-infinity) values of alpha-, gamma- and delta-tocotrienols under the fed state over those of the fasted state were found to lie between 2.24-3.40, 2.05-4.09 and 1.59-3.81, respectively, while those of the Cmax were between 2.28-4.39, 2.31-5.87 and 1.52-4.05, respectively. However, no statistically significant difference was observed between the fed and fasted Tmax values of the three homologues. The mean apparent elimination half-life (t(1/2)) of alpha-, gamma- and delta-tocotrienols was estimated to be 4.4, 4.3 and 2.3 h, respectively, being between 4.5- to 8.7-fold shorter than that reported for alpha-tocopherol. No statistically significant difference was observed between the fed and fasted t(1/2) values. The mean apparent volume of distribution (Vd/f) values under the fed state were significantly smaller than those of the fasted state, which could be attributed to increased absorption of the tocotrienols in the fed state.

Alpha- and gamma-tocotrienols are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine.

Lodge, J.K., et.al (2001). Lipids.

Limited information is available regarding metabolism of vitamin E forms, especially the tocotrienols. Carboxyethyl-hydroxychromans (alpha- and gamma-CEHC) are human urinary metabolites of alpha- and gamma-tocopherols, respectively. To evaluate whether tocotrienols are also metabolized and excreted as urinary CEHC, urine was monitored following tocotrienol supplementation. Complete (24 h) urine collections were obtained for 2 d prior to (baseline), the day of, and 2 d after human subjects (n = 6) ingested tocotrienol supplements. The subjects consumed 125 mg gamma-tocotrienyl acetate the first week, then the next week 500 mg; then 125 mg alpha-tocotrienyl acetate was administered the third week, followed by 500 mg the fourth week. Urinary alpha- and gamma-CEHC were measured by high-performance liquid chromatography with electrochemical detection. Urinary gamma-CEHC levels rose about four- to sixfold in response to the two doses of gamma-tocotrienol and then returned to baseline the following day. Significant (P < 0.0001) increases in urinary alpha-CEHC were observed only following ingestion of 500 mg alpha-tocotrienyl acetate. Typically, 1-2% of alpha-tocotrienyl acetates or 4-6% of gamma-tocotrienyl acetates were recovered as their respective urinary CEHC metabolites. A gamma-CEHC excretion time course showed an increase in urinary gamma-CEHC at 6 h and a peak at 9 h following ingestion of 125 mg gamma-tocotrienyl acetate. In summary, tocotrienols, like tocopherols, are metabolized to CEHC; however, the quantities excreted in human urine are small in relation to dose size.

In vivo / Animal Studies
Article	Study objective/ findings
Differences in the plasma transport and tissue concentrations of tocopherols and tocotrienols: observations in humans and hamsters. Hayes, K.C., et.al (1993). Proc Soc Exp Biol Med.	Certain aspects of tocopherol and tocotrienol absorption, plasma transport, and tissue distribution were examined in humans and hamsters. Plasma transport differed in that tocopherols were found primarily in low density lipoprotein and high density lipoprotein in association with plasma surface components, whereas tocotrienols disappeared from plasma with chylomicron clearance. In keeping with transport by triglyceride-rich lipoproteins, tocotrienols were deposited in conjunction with triglycerides in the adipose tissue of hamsters. In hamsters, tocopherols were the only tocol readily detected in all tissues, except adipose during tocotrienol supplementation. In fasting humans, the plasma tocotrienol concentration was not significantly increased after tocotrienol supplementation, whereas the platelet concentration of delta-tocotrienol doubled. Furthermore, tocotrienol intake did not appear to modulate the plasma cholesterol concentration in normolipemic hamsters. Thus, the transport, tissue concentration, and relative biologic function of tocopherol and tocotrienol appear somewhat disparate and possibly unrelated.

In vivo / Animal Studies

Article

Study objective/ findings

Differences in the plasma transport and tissue concentrations of tocopherols and tocotrienols: observations in humans and hamsters.

Hayes, K.C., et.al (1993). Proc Soc Exp Biol Med.

Certain aspects of tocopherol and tocotrienol absorption, plasma transport, and tissue distribution were examined in humans and hamsters. Plasma transport differed in that tocopherols were found primarily in low density lipoprotein and high density lipoprotein in association with plasma surface components, whereas tocotrienols disappeared from plasma with chylomicron clearance. In keeping with transport by triglyceride-rich lipoproteins, tocotrienols were deposited in conjunction with triglycerides in the adipose tissue of hamsters. In hamsters, tocopherols were the only tocol readily detected in all tissues, except adipose during tocotrienol supplementation. In fasting humans, the plasma tocotrienol concentration was not significantly increased after tocotrienol supplementation, whereas the platelet concentration of delta-tocotrienol doubled. Furthermore, tocotrienol intake did not appear to modulate the plasma cholesterol concentration in normolipemic hamsters. Thus, the transport, tissue concentration, and relative biologic function of tocopherol and tocotrienol appear somewhat disparate and possibly unrelated.