Dethloff L A, Watkins J R
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105-2430.
Fundam Appl Toxicol. 1992 Jul;19(1):6-14. doi: 10.1016/0272-0590(92)90022-a.
Trimetrexate was administered to rats in an interrupted treatment regimen comparable to proposed human clinical treatment. Forty-five rats of each sex were dosed intravenously with trimetrexate at 0, 1, 10, or 30 mg/kg (0, 6, 60, or 180 mg/m2), once daily for 5 consecutive days, followed by a 23-day recovery period. This cycle of dosing and recovery was repeated for a total of six cycles. Hematology, urinalysis, clinical chemistry, and gross and microscopic pathology examinations were conducted for animals euthanatized 3 and 21 days after dosing cycles 1, 3, and 6. Additional rats in each group were maintained without dosing for an additional 56 days (77 days after the last trimetrexate dose) to assess the long-term reversibility of pathologic changes. Target organs were typical for an antifolate and included gastrointestinal tract, lymphoid tissues, and the hematopoietic and male reproductive systems. No toxicity was observed at 1 mg/kg. Treatment-related changes in hematology parameters following 10 and 30 mg/kg were fully reversible within 3 weeks of each dosing cycle. Except for testis and cecum, histopathological changes were also reversible within 21 days of dosing. Trimetrexate-induced testicular changes persisting during the course of multiple cycles of dosing were not reversible within 21 days, but required an additional 56 days for essentially complete recovery.
以与拟用的人类临床治疗方案相当的间断治疗方案给大鼠施用三甲曲沙。每种性别的45只大鼠静脉注射三甲曲沙，剂量分别为0、1、10或30mg/kg（0、6、60或180mg/m²），连续5天每天一次，随后为23天的恢复期。这种给药和恢复周期总共重复6个周期。对在给药周期1、3和6后3天和21天安乐死的动物进行血液学、尿液分析、临床化学以及大体和显微镜病理学检查。每组中的另外一些大鼠在不给药的情况下再维持56天（最后一次给予三甲曲沙后77天），以评估病理变化的长期可逆性。目标器官是抗叶酸药物作用的典型靶器官，包括胃肠道、淋巴组织以及造血和雄性生殖系统。在1mg/kg剂量下未观察到毒性。10和30mg/kg剂量后血液学参数的治疗相关变化在每个给药周期的3周内完全可逆。除睾丸和盲肠外，组织病理学变化在给药21天内也可逆。在多个给药周期过程中持续存在的三甲曲沙诱导的睾丸变化在21天内不可逆，但基本上需要额外56天才能完全恢复。
