Erucylphosphocholine: pharmacokinetics, biodistribution and CNS-accumulation in the rat after intravenous administration

The clinical use of alkylphosphocholines (APC) in cancer patients is restri cted because of the high gastrointestinal toxicity and the need for oral ad ministration. Therefore we evaluated the clinical pharmacology of erucylpho sphocholine (ErPC), the first derivative of the APC family suitable for int ravenous administration with strong antineoplastic activity, in vitro and i n vivo in rats. The pharmacokinetic parameters after a single intravenous d ose of 40 mg/kg were calculated using a two-compartment model: C-max = 1.6 +/- 0.3 mu mol/ml, T-1/2 alpha = 0.18 +/- 0.09 h T-1/2 beta = 3.3 +/- 0.88 h, clearance = 9.7 +/- 1.2 ml/h, AUC = 2.5 +/- 0.3 mu mol/ml per h and Vss = 40.4 +/- 7.9 mi. Biodistribution studies were performed after repeated Er PC administration at different doses. Intravenous injections of 20 mg/kg gi ven at intervals of 48 h for up to 4 weeks were well tolerated. Neither cli nical evaluation nor laboratory parameters (haematology and clinical chemis try) revealed toxic side effects. In contrast, higher doses of ErPC (40 mg/ kg per 48 h) led to weight loss. After 2 and 4 weeks of therapy with 20 mg/ kg per 48 h a high ErPC accumulation was found in the adrenal glands, small intestine and brain. The brain to serum concentration ratios averaged 2.1 after 2 weeks and 4.5 after 4 weeks. Significant leucocytosis and thrombocy tosis were observed after 4 weeks of ErPC treatment. The findings suggest t hat ErPC is a suitable candidate for clinical trials. In particular, owing to the high accumulation in brain tissue, ErPC is a potential agent for che motherapy against malignant brain tumours.