Effect of dimethyl sulfoxide on bladder tissue penetration of intravesical paclitaxel

Abstract

Our laboratory has shown that the efficacy of bladder cancer intravesical therapy is in part limited by the poor penetration of drugs into the urothelium. We further found that paclitaxel, because of its lipophilicity, shows a higher penetration than other commonly used drugs such as mitomycin C and doxorubicin. However, the commercial formulation of paclitaxel (i.e., Taxol) contains Cremophor, which forms micelles that entrap the drug and reduce its free fraction. The present study evaluated the effect of DMSO on paclitaxel release from Cremophor micelles and paclitaxel penetration in bladders of dogs given an intravesical dose of paclitaxel (500 microg/20 ml in 0.22% Cremophor, 0.21% ethanol, and 50% DMSO). Cremophor produced a concentration-dependent reduction of the free fraction of paclitaxel (reduced to 23% at 0.25% Cremophor). This Cremophor effect was reversed by DMSO in a concentration-dependent manner, resulting in a 92% free fraction at 50% DMSO. DMSO also increased the average size of Cremophor micelles from 13 nm to 230 nm at 50% DMSO. A comparison of the tissue penetration data in the presence of Cremophor and/or DMSO indicates the following effects of DMSO: (a). increase in urine production rate and, consequently, a 36% reduction of the final urine concentration; (b). 2-fold increase in paclitaxel penetration across bladder urothelium; (c). increase in drug removal from bladder tissues (30% more rapidly); and (d). a 60% increase of the amount of drug in bladder tissue. These results indicate that DMSO caused rearrangement of Cremophor micelles, reversed the entrapment of paclitaxel in Cremophor micelles and thereby increased the free fraction of paclitaxel in solution, enhanced the urine production rate and enhanced drug removal by the perfusing capillaries, with an overall effect of increasing the bladder tissue delivery of paclitaxel formulated in Cremophor.