RT Journal Article
SR Electronic
T1 Cremophor EL-mediated Alteration of Paclitaxel Distribution in Human Blood
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 1454
OP 1457
VO 59
IS 7
A1 Sparreboom, Alex
A1 van Zuylen, Lia
A1 Brouwer, Eric
A1 Loos, Walter J.
A1 de Bruijn, Peter
A1 Gelderblom, Hans
A1 Pillay, Marrimuthoo
A1 Nooter, Kees
A1 Stoter, Gerrit
A1 Verweij, Jaap
YR 1999
UL http://cancerres.aacrjournals.org/content/59/7/1454.abstract
AB We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07 ± 0.004 (mean ± SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; i.e., 0.50%) resulted in a significant decrease in the concentration ratio (0.690 ± 0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (∼0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios. ©1999 American Association for Cancer Research.