Metabolic studies of a podophyllotoxin derivative (VP16) in the isolated perfused liver

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Abstract
The metabolism of VP16 [a potential antineoplastic agent] was studied in isolated perfused rat liver. The rate of elimination into the medium and excretion in bile were determined by HPLC [high performance liquid chromatography] with UV detection. With high VP16 concentrations (180 .mu.g/ml medium), the elimination half-life of the compound was prolonged markedly (156 vs. 45 min for lower doses), the percentage recovered in bile was more than halved and drug accumulation in the hepatic tissue was 3 times greater. These findings indicate saturation of metabolism and of biliary elimination during high-dose treatment. The presence of glucuronides in the bile of VP16 perfused livers indicates that VP16 undergoes conjugation with glucuronic acid. Formation of picro isomer of VP16 in the liver also occurs.