Pharmacokinetics, antifolate activity and tissue distribution of PT523 in SCC VII tumor-bearing mice

Purpose: To monitor the pharmacokinetics of PT523 and methotrexate in C3H mice with transplanted SCC VII tumors; to compare the impact of PT523 and methotrexate on tumor and normal host 5,10-methylenetetrahydrofolate levels; and to synthesize [14C]PT523 and determine its time-dependent tissue distribution in tumor and host tissues. Methods: C3H mice bearing SCC VII tumors were given i.p. PT523 or methotrexate. Plasma drug levels and tumor, gut and marrow 5,10-methylenetetrahydrofolate were assayed. [14C]PT523 was synthesized and administered i.v. to tumor-bearing mice for tissue distribution analysis. Results: Areas under the curve, mean residence times, whole body clearances, apparent distribution volumes, and plasma protein binding of PT523 vs methotrexate were, respectively, 4311 vs 6472 μM · min–1; 20 vs 16 min; 0.56 vs 0.36 ml · min–1; 532 vs 325 ml · kg–1; and 70% vs 30%. Both PT523 and methotrexate caused time-dependent declines in 5,10-methylenetetrahydrofolate in tumor and gut mucosa, but not in marrow. Gut levels began to recover within 4 h in the PT523-treated group only. [14C]PT523 distributed mainly into the liver, duodenum, kidneys, lungs, tumor, pancreas and muscle; less into the spleen, blood cells, heart, brain and testicles; and very little into bone marrow. Only 35% of the dose was excreted, and 2.9-fold more in feces than urine. Conclusions: Despite its more rapid clearance, accumulation of PT523 in extravascular tissues was greater than that of methotrexate. Consequently, less PT523 was recovered in feces and urine and its apparent volume of distribution was greater. PT523 selectively depleted 5,10-methylenetetrahydrofolate pools in tumor and, less persistently, in gut mucosa, but spared the marrow. [14C]PT523 tissue distribution correlated with organ mass and blood supply.