Interaction of swainsonine with lymphoid and highly perfused tissues: a pharmacokinetics explanation for sustained immunomodulation.

The kinetics of inhibition of metastasis by the immunomodulator swainsonine (SW) is effective 1 to 3 days after administration. It is likely that SW's prolonged antimetastatic effect is due to its mitogenic property (spleenocytes isolated from animals treated with SW for 42-72 hours stimulated DNA synthesis that remained elevated for up to 3 days after removal of the drug from the drinking water). An analysis of SW in lymphoid (spleen and thymus) and highly perfused tissues was undertaken to determine if SW's sustained antimetastatic effect could be correlated to its retention. C57BL/6 mice received [3H]SW in drinking water for 24-72 hours and thereafter, received SW-free drinking for 24, 48, and 72 hours. Lymphoid and highly perfused tissues were analyzed for [3H]SW. At 24, 48, and 72 hours, spleen SW levels are, respectively, at least 2.33, 2.25, and 2.00 times greater than the perfused tissue; and thymus are, respectively, 1.44, 1.50, and 1.77 as great as the perfused tissue (kidney) with the highest SW level. These studies suggest that SW is predominantly retained for at least 72 hours, in lymphoid tissue. The targeting and retention of SW for lymphoid tissue days after removal of SW from animal drinking water is consistent with a) the immunomodulatory/mitogenic property and b) the sustained antimetastatic effect attributed to SW.

A preliminary pharmacokinetic evaluation of the antimetastatic immunomodulator swainsonine: clinical and toxic implications.

The pharmacokinetics of swainsonine (SW) was investigated in mice after intravenous administration of 3 micrograms/ml. The time course of SW blood levels followed a three-compartment open pharmacokinetic model which consisted of biphasic distribution, and a rapid elimination phase (terminal half-life, 31.6 min). After completion of the distribution, SW was widely distributed to the extravascular space (Vss, 22ml; Vd, 33ml). Free fractions of this substance were indistinguishable from unity, indicating little or no protein binding. The rate-limiting step in the elimination of SW from the body appears to be the slow return from the deep compartment into the central one. Accordingly, SW blood levels may be low and yet significant amounts of this agent may be present in different body organs and tissues. A comparison of SW tissue levels indicates that the highest amounts appeared in the bladder, kidney, and thymus, (3.8 0.5, and 2.2 nmoles/g wet wt) with the lowest levels consistently appearing in the brain (< 0.1 nmoles/g wet wt). Hence, this study suggest that: 1) SW has high affinity for the thymus, which is in part consistent with its previously published immunomodulatory action; 2) SW should be infused for at least 2 1/2 hrs for its concentration to approach a plateau (this is based on the short half-life of SW and its time to steady state); and 3) CNS toxicity may be dose-limiting and not be present at SW levels preventing metastasis.