title: Bladder tissue pharmacokinetics and antitumor effect of intravesical 5-fluorouridine.
abstract: The present study evaluates whether intravesical 5-fluorouridine (FUR), a potent fluorinated pyrimidine, is effective against bladder cancer. The tissue and plasma pharmacokinetics of i.v. and intravesical FUR were studied in dogs to determine the tissue targeting advantage by the intravesical route. The i.v. study used a bolus FUR dose of 4 mg/kg, which is tolerated in humans. The disposition of FUR was biphasic, with a peak concentration of 8.8 microgram/ml and a clearance of 127 ml/min/kg. 5-Fluorouracil was the major circulating metabolite, reaching a peak concentration of 3.2 microgram/ml. In the intravesical study, FUR (approximately 2 mg/kg in 20 ml of water) was instilled in the dog bladder. At the end of the 2-h treatment, FUR concentration in urine decreased by about 40%, due mainly to dilution by residual and newly produced urine. The concentration at the interface between urothelium and lamina propria was 14 microgram/g, or approximately 2% of the urine concentration, and declined logarithmically to 2 microgram/g in the deep muscles. The concentrations of FUR and 5-fluorouracil in plasma were below the assay detection limit of 20 ng/ml, or > 200-fold lower than the concentration after the i.v. dose (adjusted to the difference in the i.v. and intravesical dose). These data indicate a > 200-fold advantage in the reduction of systemic exposure by the intravesical route. To determine whether the achievable tissue concentrations of FUR produced significant antitumor activity, we studied the effect of FUR against human bladder tumors maintained as 3-dimensional histocultures. The FUR concentrations (IC50s) required to produce 50% inhibition of DNA precursor ([3H]thymidine or bromodeoxyuridine) incorporation in human superficial bladder tumors (i.e., Ta and T1 tumors, n = 4) and muscle-invading tumors (i.e., T3 and T4 tumors, n = 4) were 9 and 22 microgram/ml, respectively. In conclusion, intravesical FUR therapy delivers effective drug concentration to superficial bladder tissues without resulting in appreciable systemic blood concentration. We propose that intravesical FUR represents a potentially effective treatment against superficial bladder cancer.
authors.affiliation: College of Pharmacy, Division of Urology, and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: D
authors.initials: D
authors.lastname: Song
authors.forename: M G
authors.initials: MG
authors.lastname: Wientjes
authors.forename: Y
authors.initials: Y
authors.lastname: Gan
authors.forename: J L
authors.initials: JL
authors.lastname: Au
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001682:Biological Availability; D004285:Dogs; D005260:Female; D005472:Fluorouracil / Q000097:blood; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D014529:Uridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001743:Urinary Bladder / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000601:surgery
chemical_list: D000903:Antibiotics, Antineoplastic; C001943:5-fluorouridine; D005472:Fluorouracil; D014529:Uridine