Hendricksen Kees, Moonen Paula M J, van der Heijden Antoine G, Molkenboer-Kuenen Janneke, Hulsbergen-van de Kaa Christina A, Witjes J Alfred
Departments of Urology and Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Clin Cancer Res. 2006 Apr 15;12(8):2597-601. doi: 10.1158/1078-0432.CCR-05-2644.
In search for a new drug for intravesical use in superficial urothelial cell carcinoma of the bladder, a pig model is used for pharmacokinetics and toxicity measurements after intravesically administered pemetrexed.
In the dose escalation phase, two groups of two pigs received 5 and 10 mg/kg pemetrexed intravesically; four groups of three pigs received 15, 20, 25, and 30 mg/kg, respectively. The well-being of the animals was monitored. Blood was studied for pharmacokinetic analysis and signs of myelosuppression. Posttreatment urine samples were collected to measure the concentration of pemetrexed after instillation. Twenty-four hours posttreatment, the animals were cystectomized and sacrificed. Histopathologic examination of the bladder wall was done. In the second study phase, five pigs were instilled weekly with the maximum tested dose for 6 weeks. The same methods were applied.
All doses (5-30 mg/kg) in the first study phase were well tolerated, enabling the use of 30 mg/kg in the second study phase. In both study phases, the pigs' well-being was not influenced. Full blood counts showed no sign of myelosuppression. Systemic absorption was not observed. Urine pemetrexed concentrations remained almost unchanged. Histopathologic examination of the bladder wall did not reveal significant abnormalities. Bladder mucosa remained intact at any time, without hemorrhage.
Intravesically administered pemetrexed in pigs is well tolerated, not absorbed systemically, and causes no bladder wall toxicity.
为寻找一种用于膀胱浅表性尿路上皮细胞癌膀胱内灌注的新药，采用猪模型对培美曲塞膀胱内给药后的药代动力学和毒性进行测定。
在剂量递增阶段，两组各两只猪分别接受5和10mg/kg培美曲塞膀胱内给药；四组各三只猪分别接受15、20、25和30mg/kg给药。监测动物的健康状况。采集血液进行药代动力学分析和骨髓抑制迹象检测。收集治疗后尿液样本以测定灌注后培美曲塞的浓度。治疗24小时后，对动物进行膀胱切除并处死。对膀胱壁进行组织病理学检查。在第二个研究阶段，五只猪每周灌注最大测试剂量，持续6周。采用相同方法。
在第一个研究阶段，所有剂量（5 - 30mg/kg）均耐受性良好，因此在第二个研究阶段可使用30mg/kg。在两个研究阶段，猪的健康状况均未受影响。全血细胞计数未显示骨髓抑制迹象。未观察到全身吸收。尿液中培美曲塞浓度几乎保持不变。膀胱壁组织病理学检查未发现明显异常。膀胱黏膜在任何时候均保持完整，无出血。
猪膀胱内灌注培美曲塞耐受性良好，无全身吸收，且不会引起膀胱壁毒性。
