Cremophor reduces paclitaxel penetration into bladder wall during intravesical treatment
Cremophor reduces paclitaxel penetration into bladder wall during intravesical treatment
复制标题
DOI：
10.1007/s002800050973
复制
发表时间：
1999-09-01
影响因子：
3
通讯作者：
Au, JLS
中科院分区：
文献类型：
--
作者：
Knemeyer, I;Wientjes, MG;Au, JLS
目的：我们之前已经证明，当紫杉醇溶解在水中并滴入膀胱时，很容易渗透尿路上皮。 FDA 批准的配方使用 Cremophor 和乙醇来溶解紫杉醇。在本研究中，评估了该溶剂系统对膀胱内紫杉醇的尿液、膀胱组织和血浆药代动力学的影响。方法：通过膀胱灌注紫杉醇（每 20 ml 500 μg 0.22% w/v Cremophor 和 0.21% v/v 乙醇）治疗 120 分钟，测定 5 只狗的血浆、尿液和组织药代动力学。使用平衡透析测定紫杉醇的游离分数，并使用荧光探针方法验证Cremophor胶束的存在。结果：膀胱组织的平均浓度比血浆浓度高 >1600 倍。将紫杉醇溶解在 Cremophor/乙醇中的结果与我们之前将紫杉醇溶解在水中（500 μg/20 ml）的结果进行比较表明，Cremophor/乙醇减少了紫杉醇在尿路上皮的分配，并使膀胱组织的平均浓度降低了 75%，但没有改变紫杉醇穿过膀胱壁的渗透率、尿液药代动力学或紫杉醇的血浆药代动力学。对于 Cremophor，120 分钟治疗期间尿液浓度为 0.12% 至 0.22%，膀胱组织中浓度为 0.00004% 至 0.0009%。胶束形成的阈值 Cremophor 浓度为 0.008%。我们发现浓度高达 1% 的乙醇和浓度低于 0.01% 的 Cremophor 不会改变紫杉醇的游离分数，而浓度较高（即 0.065% 和 0.25%）的 Cremophor 分别显着降低游离分数 2 至 6 倍。这些结果表明，在膀胱内滴注 FDA 批准的紫杉醇制剂期间，尿液中 Cremophor 的浓度足以形成胶束，导致紫杉醇被隔离在胶束中，紫杉醇的游离部分减少，从而减少紫杉醇穿过尿路上皮的渗透。相反，膀胱组织中的Cremophor浓度不足以形成胶束，因此不会改变药物通过膀胱组织的渗透。结论：我们得出的结论是，使用 FDA 批准的制剂进行膀胱内紫杉醇治疗提供了显着的膀胱组织靶向优势，尽管该优势低于紫杉醇溶解在水中时的优势。
Purpose: We have previously shown that paclitaxel, when dissolved in water and instilled into the bladder, readily penetrates the urothelium. The FDA-approved formulation uses Cremophor and ethanol to dissolve paclitaxel. In the present study, the effects of this solvent system on the urine, bladder tissue, and plasma pharmacokinetics of intravesical paclitaxel were evaluated. Methods: Plasma, urine, and tissue pharmacokinetics were determined in five dogs treated for 120 min with paclitaxel (500 mu g per 20 ml of 0.22% w/v Cremophor and 0.21% v/v ethanol) by intravesical instillation. Equilibrium dialysis was used to determine the free fraction of paclitaxel and the presence of Cremophor micelles was verified using a fluorescent probe method. Results: The average bladder tissue concentration was >1600-fold higher than the plasma concentration. Comparison of the results for paclitaxel dissolved in Cremophor/ethanol with our previous results of paclitaxel dissolved in water (500 mu g per 20 ml) indicates that Cremophor/ethanol decreased the paclitaxel partition across the urothelium and reduced the average bladder tissue concentration by 75%, but did not alter the rate of paclitaxel penetration across the bladder wall, the urine pharmacokinetics or the plasma pharmacokinetics of paclitaxel. For Cremophor, the urine concentrations during the 120-min treatment ranged from 0.12% to 0.22%, and the concentration in bladder tissue from 0.00004% to 0.0009%. The threshold Cremophor concentration for micelle formation was 0.008%. We found that ethanol at concentrations up to 1% and Cremophor at concentrations below 0.01% did not alter the free fraction of paclitaxel, whereas Cremophor at higher concentrations, i.e. 0.065% and 0.25%, significantly reduced the free fraction by two- to six-fold, respectively. These results indicate that during intravesical instillation of the FDA-approved paclitaxel formulation, the concentration of Cremophor in urine was sufficient to form micelles, resulting in sequestration of paclitaxel into micelles, reduction in the free fraction of paclitaxel and consequently a reduction in paclitaxel penetration across the urothelium. In contrast, the Cremophor concentrations in bladder tissue were inadequate to form micelles and thus did not alter the drug penetration through the bladder tissue. Conclusions: We conclude that intravesical paclitaxel treatment using the FDA-approved formulation provides a significant bladder tissue targeting advantage, although the advantage is lower than when paclitaxel is dissolved in water.