10 research outputs found
Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: in vitro and clinical pharmacokinetic studies
PURPOSE: Docosahexaenoic acid-paclitaxel is as an inert prodrug composed
of the natural fatty acid DHA covalently linked to the C2'-position of
paclitaxel (M. O. Bradley et al., Clin. Cancer Res., 7: 3229-3238, 2001).
Here, we examined the role of protein binding as a determinant of the
pharmacokinetic behavior of DHA-paclitaxel. EXPERIMENTAL DESIGN: The blood
distribution of DHA-paclitaxel was studied in vitro using equilibrium
dialysis and in 23 cancer patients receiving the drug as a 2-h i.v.
infusion (dose, 200-1100 mg/m(2)). RESULTS: In vitro, DHA-paclitaxel was
found to bind extensively to human plasma (99.6 +/- 0.057%). The binding
was concentration independent (P = 0.63), indicating a nonspecific,
nonsaturable process. The fraction of unbound paclitaxel increased from
0.052 +/- 0.0018 to 0.055 +/- 0.0036 (relative increase, 6.25%; P = 0.011)
with an increase in DHA-paclitaxel concentration (0-1000 microg/ml),
suggesting weakly competitive drug displacement from protein-binding
sites. The mean (+/- SD) area under the curve of unbound paclitaxel
increased nonlinearly with dose from 0.089 +/- 0.029 microg.h/ml (at 660
mg/m(2)) to 0.624 +/- 0.216 microg.h/ml (at 1100 mg/m(2)), and was
associated with the dose-limiting neutropenia in a maximum-effect model
(R(2) = 0.624). A comparative analysis indicates that exposure to
Cremophor EL and unbound paclitaxel after DHA-paclitaxel (at 1100 mg/m(2))
is similar to that achieved with paclitaxel on clinically relevant dose
schedules. CONCLUSIONS: Extensive binding to plasma proteins may explain,
in part, the unique pharmacokinetic profile of DHA-paclitaxel described
previously with a small volume of distribution ( approximately 4 liters)
and slow systemic clearance ( approximately 0.11 liters/h)