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[Cancer Research 59, 1454-1457, April 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 1454-1457, April 1, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Cremophor EL-mediated Alteration of Paclitaxel Distribution in Human Blood

Clinical Pharmacokinetic Implications

Alex Sparreboom1, Lia van Zuylen, Eric Brouwer, Walter J. Loos, Peter de Bruijn, Hans Gelderblom, Marrimuthoo Pillay, Kees Nooter, Gerrit Stoter and Jaap Verweij

Departments of Medical Oncology [A. S., L. v. Z., E. B., W. J. L., P. d. B., H. G., K. N., G. S., J. V.] and Nuclear Medicine [M. P.], Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3008 AE Rotterdam, the Netherlands

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.




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Copyright © 1999 by the American Association for Cancer Research.