title: Potential and toxicity of intravesical pemetrexed: a preclinical study in pigs.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Departments of Urology and Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Hendricksen
authors.forename: Paula M J
authors.initials: PM
authors.lastname: Moonen
authors.forename: Antoine G
authors.initials: AG
authors.lastname: van der Heijden
authors.forename: Janneke
authors.initials: J
authors.lastname: Molkenboer-Kuenen
authors.forename: Christina A
authors.initials: CA
authors.lastname: Hulsbergen-van de Kaa
authors.forename: J Alfred
authors.initials: JA
authors.lastname: Witjes
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004487:Edema / Q000139:chemically induced; D005260:Female; D005971:Glutamates / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D009503:Neutropenia / Q000139:chemically induced; D000068437:Pemetrexed; D013552:Swine; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D000964:Antimetabolites, Antineoplastic; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine