Je. Wright et al., PHARMACOKINETICS, ANTIFOLATE ACTIVITY AND TISSUE DISTRIBUTION OF PT523 IN SCC-VII TUMOR-BEARING MICE, Cancer chemotherapy and pharmacology, 42(4), 1998, pp. 300-306
Purpose: To monitor the pharmacokinetics of PT523 and methotrexate in
C3H mice with transplanted SCC VII tumors; to compare the impact of PT
523 and methotrexate on tumor and normal host 5,10-methylenetetrahydro
folate levels; and to synthesize [C-14]PT523 and determine its time-de
pendent tissue distribution in tumor and host tissues. Methods: C3H mi
ce bearing SCC VII tumors were given i.p. PT523 or methotrexate. Plasm
a drug levels and tumor,,out and marrow 5,10-methylenetetrahydrofolate
were assayed. [C-14]PT523 was synthesized and administered i.v. to tu
mor-bearing mice for tissue distribution analysis. Results: Areas unde
r the curve, mean residence times, whole body clearances, apparent dis
tribution volumes, and plasma protein binding of PT523 vs methotrexate
were, respectively, 4311 vs 6472 mu M.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 m
ethotrexate caused time-dependent declines in 5,10-methylenetetrahydro
folate in tumor and gut mucosa, but not in marrow. Gut levels began to
recover within 4 h in the PT523-treated group only. [C-14]PT523 distr
ibuted mainly into the liver, duodenum, kidneys, lungs, tumor, pancrea
s and muscle; less into the spleen, blood cells, heart, brain and test
icles; and very little into bone marrow. Only 35% of the dose was excr
eted, and 2.9-fold more in feces than urine. Conclusions: Despite its
more rapid clearance, accumulation of PT523 in extravascular tissues w
as greater than that of methotrexate. Consequently, less PT523 was rec
overed in feces and urine and its apparent volume of distribution was
greater. PT523 selectively depleted 5,10-methylenetetrahydrofolate poo
ls in tumor and, less persistently, in gut mucosa, but spared the marr
ow. [C-14]PT523 tissue distribution correlated with organ mass and blo
od supply.