Entrapment of methotrexate (MTX) plus [3′,5′, 9(n)-3H]methotrexate into positively charged liposomes greatly alters the subsequent distribution of [3H]MTX in a cynomolgous monkey (Macaca irus) after a single i.v. injection ([3H]MTX; refers to total radioactivity derived from purified [3H]MTX). When [3H]MTX is incorporated into small, sonically disrupted liposomes, the level of the entrapped [3H]MTX in the total plasma volume was still 50% of the total injected dose after 4 hr, which is 100 times greater than the level found when the same amount of free MTX (1 to 4 mg) plus [3H]MTX was injected. When entrapped in larger mechanically dispersed liposomes, however, the plasma levels of liposome-entrapped [3H]MTX at 4 hr was only 6-fold greater than free [3H]MTX. The liposome-entrapped MTX (refers to MTX measured by dihydrofolate reductase assay) did not show detectable breakdown in the plasma whereas free MTX showed up to 97% breakdown.

Increased clearance of [3H]MTX entrapped in mechanically dispersed liposomes was complemented by its much greater uptake into tissues, especially spleen, compared with sonically disrupted liposomes. There was over a 160-fold increased uptake by the spleen of liposome-entrapped [3H]MTX relative to free [3H]MTX, whereas for sonically disrupted liposomes the comparable ratio was 20. Although this liposome-entrapped MTX showed significant breakdown, it was less than that found after injection of free MTX. In certain tissues, especially the small intestine, a reduced uptake of liposome-entrapped [3H]MTX was found. Uptake of liposome-entrapped [3H]MTX into liposomes led to a much lower renal clearance of [3H]MTX, especially in the case of sonically disrupted liposomes. Possible reasons for these effects and the relationship of our findings to those of others are discussed.


This study was supported by Grant CA 17516 from NIH.

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