Our objective was to assess the distribution of
paclitaxel in plasma and cerebrospinal fluid (CSF) in a
cancer patient, and evaluate the role of the formulation vehicle
Cremophor EL (CrEL) in
drug distribution. Analysis of
paclitaxel concentrations in CSF was performed using a triple-quadrupole mass spectrometric assay with electrospray ionization. Total and unbound
paclitaxel levels in plasma were measured by liquid chromatography and equilibrium dialysis, respectively, and CrEL concentrations were determined by a colorimetric
dye-binding microassay. Clinical samples were obtained from a 54-year-old female with
breast cancer receiving a weekly regimen of
paclitaxel (dose 60 mg/m2). The disposition of total
paclitaxel in plasma was characterized by a bi-exponential elimination (terminal half-life 9.17 h) and a total clearance of 19.4 l/h/m2. The fraction of unbound
paclitaxel in plasma ranged from 7.6 to 12.4% (unbound
drug CL 176 l/h/m2). The plasma clearance of CrEL was 0.332 l/h/m2, whereas CrEL levels were undetectable in CSF (below 0.5 microl/ml). Concentrations of
paclitaxel in CSF (range 45.5-162 pg/ml) and unbound CSF:unbound plasma concentration ratios (range 0.093-9.53%) progressively increased up to 24 h, with a mean unbound
drug fraction in CSF of 84+/-3.6% (range 81-88%). These findings indicate that there is substantial distribution of
paclitaxel to CSF. Since the fraction of unbound
paclitaxel is different between plasma and CSF, measurement of unbound
paclitaxel is required to accurately assess the extent of
drug penetration.