title: Fate of tritiated didemnin B in mice: excretion and tissue concentrations after an intraperitoneal dose.
abstract: Didemnin B has undergone trials in cancer patients, and has antiviral and immunosuppressive properties. [(3)H]didemnin B was administered intraperitoneally (i.p.) to mice at 320 or 1280 microg/kg. Urine and feces were collected until 168 h, at which time the mice were killed and tissues collected. Additionally, [(3)H]didemnin B was given i.p. at 320 microg/kg, and mice were killed at 1-120 h post-dosing. Radiolabel increased rapidly in blood then rapidly declined. Most radiolabel in urine, feces and tissues represented parent compound. Concentrations of [(3)H]didemnin B were greatest in the liver > gallbladder > lower digestive tract congruent with pancreas > spleen > kidney congruent with adipose tissue congruent with urinary bladder with urine. The pancreas had the longest terminal half-life of the tissues and the highest radioactivity at 7 days. Intermediate concentrations were in the duodenum congruent with jejunum > lung > iliopsoas > stomach congruent with testes congruent with skin > heart. Low concentrations were in the humerus congruent with femur congruent with quadriceps congruent with triceps >> brain. Fecal excretion accounted for 45.9%-58.3% of the dose and declined after 24 h, followed by an increase, suggesting possible enterohepatic recycling or an impact of circadian rhythms. Urinary excretion accounted for 18.4%-25.2% of the dose, but was minimal after 24 h. The concentrations were highest in organs previously found to be sensitive in animals and humans. Didemnin B should be evaluated in animal models for treatment of pancreatic cancer.
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL 61801, USA. val@uiuc.edu
authors.forename: Val R
authors.initials: VR
authors.lastname: Beasley
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Bruno
authors.forename: John S
authors.initials: JS
authors.lastname: Burner
authors.forename: Byoung W
authors.initials: BW
authors.lastname: Choi
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rinehart
authors.forename: Gary D
authors.initials: GD
authors.lastname: Koritz
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Levengood
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D047630:Depsipeptides / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D014018:Tissue Distribution; D014316:Tritium
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D047630:Depsipeptides; D007166:Immunosuppressive Agents; D014316:Tritium; C030051:didemnins