Pharmacokinetics of vinblastine in rat blood plasma and tumour tissue determined by a biological method using flow cytofluorimetry

For the optimal use of vinblastine as an antineoplastic agent, knowledge of the pharmacokinetic distribution in blood plasma and tumour tissue is necessary. A method is presented for the determination of mitotic inhibitory activity of vinblastine and its metabolites, extracted from tissue samples. With this method concentrations as low as0.005 mg/l which are biologically active can be reproducibly determined.The method has been applied to follow the concentration of vinblastine in blood plasma and tumour tissue after injection of1.5 mg of vinblastine/kg body weight in WAG/Rij rats with aR-1, M tumour of0.3–1.0 g growing in the flank. The high concentration in plasma immediately after i.v. injection decreases quickly within24 hr to the minimal detectable concentration in plasma of0.01 mg/l. Although after i.p. injection the concentration in plasma is lower initially, at24 hr it tends to be higher than after i.v. injection. In tumour tissue the maximal concentration is reached at6 hr after i.v. injection (3.0 mg/kg) and at12 hr after i.p. injection (0.6 mg/kg). From12 hr after i.p. injection the concentration remains constant during2–3 days while after i.v. injection a slow decrease is observed. These pharmacokinetic data are compared with the changes of cell proliferation kinetics in the tumour induced by vinblastine. The finding that after i.v. injection the maximal concentration in tumour tissue is higher and is reached earlier than after i.p. injection correlates well with the higher degree of accumulation of cells in mitosis.