Pharmacokinetics and tissue distribution of d-alpha-tocopheryl succinate formulations following intravenous...

Unlike d-alpha tocopherol (T), d-alpha tocopheryl succinate (TS) has the unique ability to selectively kill tumor cells while protecting normal tissue from toxic oxidative stress. The pharmacokinetics of TS and the serum and tissue disposition of TS were studied in male Sprague-Dawley rats to delineate formulation dependent disposition between TS administered as the Tris salt (TS-T) (a liposomal formulation) or as the free acid (TS-FA) dissolved in polyethylene glycol (PEG) 400. The pharmacokinetics of TS was studied after single intravenous (i.v.) equimolar doses of 124 mg/kg TS-T and 100 mg/kg of TS-FA. Serial blood samples were collected via a catheter inserted into the right jugular vein and serum samples were analysed for TS and T levels using a reverse phase HPLC method. Terminal tissue samples were also collected at 24 and 48 h. After an acute i.v. dose of TS-T, serum AUC, t(1/2), Cl and V(d) of TS were 2601.0 +/- 351.7 microg h/ml, 9.98 +/- 1.02 h, 0.049 +/- 0. 0073 l/h/kg and 0.7 +/- 0.14 l/kg (mean +/- SD), respectively. The acute i.v. administration of TS-FA (PEG formulation) yielded results similar to those observed for TS-T, with a serum AUC, t(1/2), Cl and V(d) of 2553.3 +/- 166.4 microg h/ml, 9.83 +/- 0.86 h, 0.039 +/- 0.0027 l/h/kg and 0.56 +/- 0.09 l/kg (mean +/- SD), respectively. Distribution into tissues and a low Cl was apparent, with the highest concentrations of TS in the liver and lung, regardless of formulation. As expected, baseline endogenous concentrations of T were present in both groups, with a net increase in T levels, occurring as TS was hydrolysed to T, which slowly peaked in serum between 7-8 h post-dose. Intravenous TS administration, regardless of formulation, also resulted in significant T accumulation in all tissues examined, which was especially abundant in the liver and lung. Likewise, there was a lack of significant effect of formulation on the pharmacokinetics and tissue distribution of TS. The only significant formulation difference was a small but significant increase in serum T and liver T levels in the TS in PEG formulation group. These results indicate that TS may be especially useful for the targeted delivery of T and TS to the lung and liver for anti-oxidant and anti-cancer activity.