title: Pharmacokinetics, antifolate activity and tissue distribution of PT523 in SCC VII tumor-bearing mice.
abstract: OBJECTIVE
  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 microM x min(-1); 20 vs 16 min; 0.56 vs 0.36 ml min(-1); 532 vs 325 ml x kg(-1); and 70% vs 30%. Both PT523 and methotrexate caused time-dependent declines in 5,10-methylenetetrahydrofolate in tumor and marrow, but not in gut mucosa [corrected]. 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 gut [corrected. 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 marrow, but spared the gut mucosa [corrected]. [14C]PT523 tissue distribution correlated with organ mass and blood supply.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Wright
authors.forename: M
authors.initials: M
authors.lastname: Pardo
authors.forename: A
authors.initials: A
authors.lastname: Tretyakov
authors.forename: W L
authors.initials: WL
authors.lastname: Alperin
authors.forename: D
authors.initials: D
authors.lastname: Trites
authors.forename: A
authors.initials: A
authors.lastname: Rosowsky
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002250:Carbon Radioisotopes; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000378:metabolism*; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011622:Pterins / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D013763:Tetrahydrofolates / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D005493:Folic Acid Antagonists; D011622:Pterins; D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; C085590:N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine; D009952:Ornithine; D008727:Methotrexate