Wright J E, Pardo M, Tretyakov A, Alperin W L, Trites D, Rosowsky A
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cancer Chemother Pharmacol. 1998;42(4):300-6. doi: 10.1007/s002800050821.
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.
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.
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.
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.
监测PT523和甲氨蝶呤在移植有SCC VII肿瘤的C3H小鼠体内的药代动力学；比较PT523和甲氨蝶呤对肿瘤及宿主正常组织中5,10-亚甲基四氢叶酸水平的影响；合成[14C]PT523并确定其在肿瘤和宿主组织中的时间依赖性组织分布。
给荷SCC VII肿瘤的C3H小鼠腹腔注射PT523或甲氨蝶呤。测定血浆药物水平以及肿瘤、肠道和骨髓中的5,10-亚甲基四氢叶酸。合成[14C]PT523并静脉注射给荷瘤小鼠以进行组织分布分析。
PT523与甲氨蝶呤的曲线下面积、平均驻留时间、全身清除率、表观分布容积和血浆蛋白结合率分别为4311对6472 μM·min-1；20对16分钟；0.56对0.36 ml·min-1；532对325 ml·kg-1；以及70%对30%。PT523和甲氨蝶呤均导致肿瘤和骨髓中5,10-亚甲基四氢叶酸随时间下降，但肠道黏膜中未出现这种情况[校正后]。仅在PT523治疗组中，肠道水平在4小时内开始恢复。[14C]PT523主要分布到肝脏、十二指肠、肾脏、肺、肿瘤、胰腺和肌肉；较少分布到脾脏、血细胞、心脏、大脑和睾丸；极少分布到肠道[校正后]。仅35%的剂量被排泄，粪便中的排泄量是尿液中的2.9倍。
尽管PT523清除更快，但其在血管外组织中的蓄积大于甲氨蝶呤。因此，粪便和尿液中回收的PT523较少，其表观分布容积更大。PT523选择性地耗尽肿瘤中以及在骨髓中持续时间较短的5,10-亚甲基四氢叶酸池，但未累及肠道黏膜[校正后]。[14C]PT523的组织分布与器官质量和血液供应相关。
