Wientjes M G, Badalament R A, Au J L
College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Cancer Chemother Pharmacol. 1996;37(6):539-46. doi: 10.1007/s002800050426.
The bladder wall penetration kinetics of intravesical doxorubicin were examined in radical cystectomy patients, to provide insight into drug concentrations at target tumor sites. The dosing solution (40 mg/20 ml) was instilled just prior to the start of surgery and maintained for 60-115 min until just prior to bladder excision. The data showed considerable inter-patient variability in the peak plasma concentration (24-fold), urine concentration (7- fold), and tissue concentration (28-fold). The urine concentration at the time of tissue harvest was about 17% of the concentration in the dosing solution. This was due to the dilution by post-catheterization residual urine and urine produced during treatment. The doxorubicin concentration dropped by 32-fold across the urothelium, and declined semi-logarithmically with respect to depth in the capillary-perfused tissues beneath the urothelium with a 50% decrease over about 500 micromole. In three of six patients from whom tumor tissue was obtained, the doxorubicin concentration was higher than the adjacent non-tumor-bearing tissues of comparable tissue depth, whereas the reverse was seen in the remaining three tumors. The plasma concentrations were 0.02, 0.03, 0.05, 0.27, and 0.69% of the concentrations in the tumors, urothelium, lamina propria, superficial and deep muscle layers, respectively. These data indicate: (a) a considerable intra- and inter-patient variability in bladder tissue concentrations, in part due to the variability in the urine concentration; (b) the urothelium is an effective barrier to doxorubicin penetration; and (c) a targeting advantage of intravesical therapy for the treatment of superficial bladder cancer yielding superficial bladder tissue concentrations at least 2000-fold higher than in the systemic circulation. A comparison of the data of doxorubicin with our previously published data on mitomycin C shows similar bladder tissue pharmacokinetics for the two drugs, suggesting that there is no pharmacokinetic preference for either drug.
在根治性膀胱切除术患者中研究了膀胱内多柔比星的膀胱壁渗透动力学，以深入了解靶肿瘤部位的药物浓度。给药溶液（40mg/20ml）在手术开始前即刻注入，并维持60 - 115分钟，直至膀胱切除前。数据显示患者间在血浆峰值浓度（24倍）、尿液浓度（7倍）和组织浓度（28倍）方面存在相当大的变异性。组织采集时的尿液浓度约为给药溶液浓度的17%。这是由于导尿后残余尿液和治疗期间产生的尿液的稀释作用。多柔比星浓度在整个尿路上皮下降了32倍，并且相对于尿路上皮下方毛细血管灌注组织中的深度呈半对数下降，在约500微米内下降50%。在获取肿瘤组织的6例患者中的3例中，多柔比星浓度高于相邻的、组织深度相当的非肿瘤组织，而在其余3个肿瘤中则相反。血浆浓度分别为肿瘤、尿路上皮、固有层、浅肌层和深肌层浓度的0.02%、0.03%、0.05%、0.27%和0.69%。这些数据表明：（a）患者内和患者间膀胱组织浓度存在相当大的变异性，部分原因是尿液浓度的变异性；（b）尿路上皮是多柔比星渗透的有效屏障；（c）膀胱内治疗浅表性膀胱癌的靶向优势在于产生的浅表膀胱组织浓度比全身循环中的浓度至少高2000倍。多柔比星的数据与我们先前发表的丝裂霉素C的数据比较显示，两种药物的膀胱组织药代动力学相似，表明两种药物在药代动力学上没有偏好。
