Gao X, Au J L, Badalament R A, Wientjes M G
College of Pharmacy, Ohio State University, Columbus 43210, USA.
Clin Cancer Res. 1998 Jan;4(1):139-43.
The design of an ongoing Phase III study of intravesical mitomycin C therapy to treat bladder cancer is partly based on the assumption that drug penetration into bladder tissue is linearly related to drug concentration. The present study was designed to (a) test this assumption and (b) to compare drug concentrations in tumor and adjacent normal tissues in human bladders. We previously reported the uptake kinetics of a 20-mg dose in dog and human bladders (M. G. Wientjes et al., Cancer Res., 51: 4347-4354, 1991, and Cancer Res., 53: 3314-3320, 1993). The present study used a 40 mg/20 ml dose. Serial blood and urine samples were taken from dogs during the 120-min instillation. Bladder tissues were harvested from dogs and patients at the end of instillation. A comparison of the results of the present and previous studies indicates identical tissue penetration kinetic parameters in dogs for the two doses, i.e., a approximately 30-fold concentration drop across the urothelium and a half-width of approximately 500 microns. In addition, the average tissue concentration in dog and human bladders attained with the 40-mg dose (8.77 micrograms/g in dogs and 7.55 micrograms/g in humans) was about twice that achieved with the 20-mg dose (4.33 micrograms/g in dogs and 3.91 micrograms/g in humans). In dogs, the plasma concentration of MMC reached a steady state within 10 min; the mean maximal plasma concentration was 8.5 ng/ml. This plasma concentration is indistinguishable from the concentration derived from the 20-mg dose and indicates a minimal systemic exposure even at the higher dose. The average MMC concentration in tumor-bearing tissues was about 40% higher than the concentration in adjacent normal tissues (P = 0.01). In conclusion, the linear relationship between drug uptake in bladder tissues and drug concentration in urine supports the assumption used in the design of the ongoing Phase III clinical trial.
一项正在进行的膀胱内注射丝裂霉素C治疗膀胱癌的III期研究设计部分基于这样一个假设，即药物渗透到膀胱组织中的程度与药物浓度呈线性关系。本研究旨在：（a）验证这一假设；（b）比较人膀胱肿瘤组织和相邻正常组织中的药物浓度。我们之前报道了20mg剂量在犬类和人类膀胱中的摄取动力学（M.G.温特耶斯等人，《癌症研究》，51:4347 - 4354，1991年，以及《癌症研究》，53:3314 - 3320，1993年）。本研究使用了40mg/20ml的剂量。在120分钟的滴注过程中，从犬类身上采集系列血液和尿液样本。滴注结束时，从犬类和患者身上获取膀胱组织。对本研究和之前研究结果的比较表明，两种剂量在犬类中的组织渗透动力学参数相同，即跨尿路上皮的浓度下降约30倍，半峰宽约为500微米。此外，40mg剂量在犬类和人类膀胱中达到的平均组织浓度（犬类为8.77微克/克，人类为7.55微克/克）约为20mg剂量（犬类为4.33微克/克，人类为3.91微克/克）的两倍。在犬类中，MMC的血浆浓度在10分钟内达到稳态；平均最大血浆浓度为8.5ng/ml。该血浆浓度与20mg剂量得出的浓度无差异，表明即使在较高剂量下全身暴露也极小。荷瘤组织中的MMC平均浓度比相邻正常组织中的浓度高约40%（P = 0.01）。总之，膀胱组织中药物摄取与尿液中药物浓度之间的线性关系支持了正在进行的III期临床试验设计中所采用的假设。
