Potential and Toxicity of Intravesical Pemetrexed: a Preclinical Study in Pigs
Purpose: In search for a new drug for intravesical use in superficial urothelial cell carcinoma of the bladder, a pig model is used for pharmacokinetics and toxicity measurements after intravesically administered pemetrexed. Experimental Design: In the dose escalation phase, two groups of two pigs r...
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Veröffentlicht in: | Clinical cancer research 2006-04, Vol.12 (8), p.2597-2601 |
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Zusammenfassung: | Purpose: In search for a new drug for intravesical use in superficial urothelial cell carcinoma of the bladder, a pig model is used
for pharmacokinetics and toxicity measurements after intravesically administered pemetrexed.
Experimental Design: In the dose escalation phase, two groups of two pigs received 5 and 10 mg/kg pemetrexed intravesically; four groups of three
pigs received 15, 20, 25, and 30 mg/kg, respectively. The well-being of the animals was monitored. Blood was studied for pharmacokinetic
analysis and signs of myelosuppression. Posttreatment urine samples were collected to measure the concentration of pemetrexed
after instillation. Twenty-four hours posttreatment, the animals were cystectomized and sacrificed. Histopathologic examination
of the bladder wall was done. In the second study phase, five pigs were instilled weekly with the maximum tested dose for
6 weeks. The same methods were applied.
Results: All doses (5-30 mg/kg) in the first study phase were well tolerated, enabling the use of 30 mg/kg in the second study phase.
In both study phases, the pigs' well-being was not influenced. Full blood counts showed no sign of myelosuppression. Systemic
absorption was not observed. Urine pemetrexed concentrations remained almost unchanged. Histopathologic examination of the
bladder wall did not reveal significant abnormalities. Bladder mucosa remained intact at any time, without hemorrhage.
Conclusions: Intravesically administered pemetrexed in pigs is well tolerated, not absorbed systemically, and causes no bladder wall toxicity. |
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-05-2644 |