Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Sep;81(2):330–335. doi: 10.1038/sj.bjc.6690696

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

O van Tellingen 1, M T Huizing 2, V R Nannan Panday 2, J H M Schellens 1, W J Nooijen 1, J H Beijnen 2
PMCID: PMC2362856  PMID: 10496361

Abstract

The non-linear plasma pharmacokinetics of paclitaxel in patients has been well established, however, the exact underlying mechanism remains to be elucidated. We have previously shown that the non-linear plasma pharmacokinetics of paclitaxel in mice results from Cremophor EL. To investigate whether Cremophor EL also plays a role in the non-linear pharmacokinetics of paclitaxel in patients, we have established its pharmacokinetics in patients receiving paclitaxel by 3-, 24- or 96-h intravenous infusion. The pharmacokinetics of Cremophor EL itself was non-linear as the clearance (Cl) in the 3-h schedules was significantly lower than when using the longer 24- or 96-h infusions (Cl175–3 h = 42.8 ± 24.9 ml h−1 m−2; Cl175–24 h = 79.7 ± 24.3; P = 0.035 and Cl135–3 h = 44.1 ± 21.8 ml h−1 m−1; Cl140–96 h = 211.8 ± 32.0; P < 0.001). Consequently, the maximum plasma levels were much higher (0.62%) in the 3-h infusions than when using longer infusion durations. By using an in vitro equilibrium assay and determination in plasma ultrafiltrate we have established that the fraction of unbound paclitaxel in plasma is inversely related with the Cremophor EL level. Despite its relatively low molecular weight, no Cremophor EL was found in the ultrafiltrate fraction. Our results strongly suggest that entrapment of paclitaxel in plasma by Cremophor EL, probably by inclusion in micelles, is the cause of the apparent nonlinear plasma pharmacokinetics of paclitaxel. This mechanism of a (pseudo-)non-linearity contrasts previous postulations about saturable distribution and elimination kinetics and means that we must re-evaluate previous assumptions on pharmacokinetics–pharmacodynamics relationships. © 1999 Cancer Research Campaign

Keywords: in vitro dialysis, plasma ultrafiltrate, free fraction, pharmacokinetic–pharmacodynamic relationship

Full Text

The Full Text of this article is available as a PDF (81.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Gengo F. M., Schentag J. J., Jusko W. J. Pharmacokinetics of capacity-limited tissue distribution of methicillin in rabbits. J Pharm Sci. 1984 Jul;73(7):867–873. doi: 10.1002/jps.2600730703. [DOI] [PubMed] [Google Scholar]
  2. Gianni L., Kearns C. M., Giani A., Capri G., Viganó L., Lacatelli A., Bonadonna G., Egorin M. J. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol. 1995 Jan;13(1):180–190. doi: 10.1200/JCO.1995.13.1.180. [DOI] [PubMed] [Google Scholar]
  3. Huizing M. T., Giaccone G., van Warmerdam L. J., Rosing H., Bakker P. J., Vermorken J. B., Postmus P. E., van Zandwijk N., Koolen M. G., ten Bokkel Huinink W. W. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre. J Clin Oncol. 1997 Jan;15(1):317–329. doi: 10.1200/JCO.1997.15.1.317. [DOI] [PubMed] [Google Scholar]
  4. Huizing M. T., Keung A. C., Rosing H., van der Kuij V., ten Bokkel Huinink W. W., Mandjes I. M., Dubbelman A. C., Pinedo H. M., Beijnen J. H. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol. 1993 Nov;11(11):2127–2135. doi: 10.1200/JCO.1993.11.11.2127. [DOI] [PubMed] [Google Scholar]
  5. Huizing M. T., Misser V. H., Pieters R. C., ten Bokkel Huinink W. W., Veenhof C. H., Vermorken J. B., Pinedo H. M., Beijnen J. H. Taxanes: a new class of antitumor agents. Cancer Invest. 1995;13(4):381–404. doi: 10.3109/07357909509031919. [DOI] [PubMed] [Google Scholar]
  6. Huizing M. T., Sparreboom A., Rosing H., van Tellingen O., Pinedo H. M., Beijnen J. H. Quantification of paclitaxel metabolites in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl. 1995 Dec 15;674(2):261–268. doi: 10.1016/0378-4347(95)00308-8. [DOI] [PubMed] [Google Scholar]
  7. Kearns C. M., Gianni L., Egorin M. J. Paclitaxel pharmacokinetics and pharmacodynamics. Semin Oncol. 1995 Jun;22(3 Suppl 6):16–23. [PubMed] [Google Scholar]
  8. Meerum Terwogt J. M., Beijnen J. H., ten Bokkel Huinink W. W., Rosing H., Schellens J. H. Co-administration of cyclosporin enables oral therapy with paclitaxel. Lancet. 1998 Jul 25;352(9124):285–285. doi: 10.1016/s0140-6736(98)24030-x. [DOI] [PubMed] [Google Scholar]
  9. Rischin D., Webster L. K., Millward M. J., Linahan B. M., Toner G. C., Woollett A. M., Morton C. G., Bishop J. F. Cremophor pharmacokinetics in patients receiving 3-, 6-, and 24-hour infusions of paclitaxel. J Natl Cancer Inst. 1996 Sep 18;88(18):1297–1301. doi: 10.1093/jnci/88.18.1297. [DOI] [PubMed] [Google Scholar]
  10. Rowinsky E. K., Donehower R. C. Paclitaxel (taxol) N Engl J Med. 1995 Apr 13;332(15):1004–1014. doi: 10.1056/NEJM199504133321507. [DOI] [PubMed] [Google Scholar]
  11. Sonnichsen D. S., Hurwitz C. A., Pratt C. B., Shuster J. J., Relling M. V. Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors. J Clin Oncol. 1994 Mar;12(3):532–538. doi: 10.1200/JCO.1994.12.3.532. [DOI] [PubMed] [Google Scholar]
  12. Sparreboom A., Loos W. J., Verweij J., de Vos A. I., van der Burg M. E., Stoter G., Nooter K. Quantitation of Cremophor EL in human plasma samples using a colorimetric dye-binding microassay. Anal Biochem. 1998 Jan 15;255(2):171–175. doi: 10.1006/abio.1997.2467. [DOI] [PubMed] [Google Scholar]
  13. Sparreboom A., Verweij J., van der Burg M. E., Loos W. J., Brouwer E., Viganò L., Locatelli A., de Vos A. I., Nooter K., Stoter G. Disposition of Cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. Clin Cancer Res. 1998 Aug;4(8):1937–1942. [PubMed] [Google Scholar]
  14. Sparreboom A., van Tellingen O., Huizing M. T., Nooijen W. J., Beijnen J. H. Determination of polyoxyethyleneglycerol triricinoleate 35 (Cremophor EL) in plasma by pre-column derivatization and reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Appl. 1996 Jun 7;681(2):355–362. doi: 10.1016/0378-4347(95)00544-7. [DOI] [PubMed] [Google Scholar]
  15. Sparreboom A., van Tellingen O., Nooijen W. J., Beijnen J. H. Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res. 1996 May 1;56(9):2112–2115. [PubMed] [Google Scholar]
  16. Sparreboom A., van Tellingen O., Nooijen W. J., Beijnen J. H. Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs. 1996 Jan;7(1):78–86. doi: 10.1097/00001813-199601000-00009. [DOI] [PubMed] [Google Scholar]
  17. Webster L., Linsenmeyer M., Millward M., Morton C., Bishop J., Woodcock D. Measurement of cremophor EL following taxol: plasma levels sufficient to reverse drug exclusion mediated by the multidrug-resistant phenotype. J Natl Cancer Inst. 1993 Oct 20;85(20):1685–1690. doi: 10.1093/jnci/85.20.1685. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES