The in vitro rabbit whole bladder as a model to investigate the urothelial transport of anticancer agents The ONCOFID-P paradigm.
Intravesical instillation of BCG or anticancer agents after transurethral resection is currently considered a standard of therapy. However, this approach is basically empirical; none of the anticancer agents used in this setting was specifically formulated for intravesical therapy. Moreover, concern is raised by the kinetic features of water soluble drugs, because of poor transport across the mucosal barrier, or of liphophylic compounds, for the increased risks of systemic toxicity. A need exists to improve the pre-clinical and clinical approaches used at present to test anticancer agents undergoing specific development for intravesical use. We used in vitro rabbit whole bladders as a new pre-clinical model to investigate the kinetics of locally administered anticancer agents. In this study, we investigated the rate of urothelial transport of a novel paclitaxel derivative, Oncofid-P. Male New Zealand albino rabbits were used. Bladders were rapidly explanted, filled with vehicle alone or vehicle containing graded concentrations of Oncofid-P, and kept for various times under standardized incubation conditions. At the end of experiments, drug concentrations were assessed by high-pressure-liquid-chromatography technique in the intravesical and external bath solutions, as well as in bladder wall homogenates. We found that less than 1% of the drug additioned to the intravesical solution is recovered within the bladder wall in the form of paclitaxel; experiments carried out collecting different areas from the same bladders showed that Oncofid-P is uniformly distributed over the internal surface of bladder mucosa. Isolated rabbit bladders may be a useful pre-clinical model to investigate the rate of transport of chemotherapeutic agents administered by intravesical route. In this paradigm, Oncofid-P displays a kinetic profile that is predictive of local activity over the whole urothelial surface, and low or absent systemic absorption.
Tringali
Giuseppe
G
Institute of Pharmacology, Catholic University Medical School, Largo Francesco Vito 1, 00168 Rome, Italy.
Lisi
Lucia
L
Bettella
Fabio
F
Renier
Davide
D
Di Stasi
Savino M
SM
Navarra
Pierluigi
P
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D006820:Hyaluronic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D017239:Paclitaxel / Q000493:pharmacokinetics*; D011817:Rabbits; D013056:Spectrophotometry, Ultraviolet; D001743:Urinary Bladder / Q000378:metabolism*; D019459:Urothelium / Q000378:metabolism*
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D006820:Hyaluronic Acid; D017239:Paclitaxel