PACLITAXEL DISPOSITION IN PLASMA AND CENTRAL NERVOUS SYSTEMS OF HUMANS AND RATS WITH BRAIN-TUMORS

Background: Paclitaxel (Taxol) has been shown to sensitize some malign ant cells to the effects of radiation, A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to ex ploit this phenomenon, The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissu e being radiated, Paclitaxel is known to have limited access to the ce ntral nervous system (CNS) of rats and mice, but its ability to penetr ate malignant tissue in the CNS is inadequately documented, Purpose: O ur purpose was to examine the concentrations of paclitaxel in the cere brospinal fluid (CSF) of patients with CNS malignancies and normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concom itant paclitaxel concentrations in the plasma of those same patients a nd animals, Methods: Four patients were treated with 3-hour infusions of paclitaxel at doses between 90 and 200 mg/m(2), Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of th e paclitaxel infusion, Four Fischer rats had 20 000 C6 glioma cells st ereotactically implanted into their right frontal lobes; 28 days later , they were given 3-hour infusions of paclitaxel at 10 mg/kg, Plasma w as sampled during the paclitaxel infusion, At the completion of the in fusion, rats were killed, and portions of their normal and malignant C NS tissues were removed for histologic assessment, Concentrations of p aclitaxel in plasma, CSF, and brain tissue were determined with high-p ressure liquid chromatography. Results: Plasma pharmacokinetics of pac litaxel in patients with brain tumors were comparable to those previou sly described in patients with other malignancies, Paclitaxel could be measured in CSF of all patients, but concentrations were very low, Pe ak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occ urred between 3.25 and 5 hours after initiation of the paclitaxel infu sion, Peak paclitaxel concentrations in CSF were between 0.12% and 8.3 % of those present in concomitant plasma samples, Paclitaxel was not d etectable in the normal or malignant CNS tissue of any rat, despite th e fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 mu M, Conclusions: Paclitaxel has only limited access to the CSF of patients with CNS malignancies and t o normal and malignant CNS tissues of rats bearing brain tumors, Impli cations: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documente d limited access of paclitaxel to the CNS.