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.