Paclitaxel pharmacokinetics are nonlinear with saturable metabolism and sat
urable distribution to the tissues. The saturable distribution has in previ
ous pharmacokinetic modeling been described as a saturable transport proces
s, whereas the present study was undertaken to investigate alternative expl
anations. Using a sparse sampling scheme (on average 3.3 samples per profil
e), 101 plasma concentration-time profiles in 22 female patients with metas
tatic cancer of the breast or ovary were monitored. It was found that the o
bserved data could be equally well described by saturable tissue binding as
well as by capacity-limited tissue transport. The data were better describ
ed by a model where equilibrium was achieved with drug in the central rathe
r than in the peripheral compartment. Models where the binding was assumed
to be an instantaneous or a noninstantaneous process were tried, but the da
ta did not allow resolution between these two possibilities. The value at w
hich the saturable transport was half-maximal was 0.55 mu M. The K-d values
of the binding models were 0.06 to 0.12 mu M. These are close to the value
s reported as a threshold for drug toxicity of paclitaxel, suggesting a pos
sible connection between the binding sites involved in the pharmacokinetics
and the mechanism responsible for the toxicity. For all models, a saturabl
e elimination of paclitaxel was included using the Michaelis-Menten model.
K-m for the elimination ranged in the different models from 2.5 to 5.6 mu M
.