Toxicity of Novel Solubilizer of Paclitaxel, Aceporol 330, in Beagle Dogs

  • Published : 2008.03.28


In order to develop an improved paclitaxel formulation vehicle, a micelle forming solubilizer, Aceporol 330 was synthesized. It was previously reported that Aceporol 330 provided the linearity of paclitaxel plasma pharmacokinetics. In this study, the single dose toxicity test and 2-week repeated dose toxicity test of Aceporol 330 was performed in beagle dogs after intravenous administration. Single dose and 2-week repeated dose toxicity test of Aceporol 330 showed fever/generalized erythema, severe vomiting, and diarrhea in beagle dogs. However, those toxicities were less severe than those of Cremophor EL. Blood chemistry analysis of 2-week repeatedly treated beagle dogs with Aceporol 330 showed significant elevation of total cholesterol (TCHO) and triglyceride (TG) compared to that of control group. Cremophor EL also significantly increased total cholesterol (TCHO) and triglyceride (TG) as much as Aceporol 330. Results from this study indicated that Aceporol 330 was less toxic than Cremophor EL. Based on the pharmacokinetic advantages and the low toxicity of Aceporol 330 in single dose and 2-week repeated dose toxicity test, Aceporol 330 has a potential for use as a safer solubilizer for paclitaxel than Cremophor EL.



  1. Cai S., Vijayan K., Cheng D., Lima E. M. and Discher D. E. (2007). Micelles of different morphologies--advantages of worm-like filomicelles of PEO-PCL in paclitaxel delivery. Pharm. Res. 24(11), 2099-109
  2. Gelderblom H., Verweij J., Nooter K. and Sparreboom A. (2001). Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur. J. Cancer. 37(13), 1590-8
  3. Jeong E. J., Han S. C., Cha S. W., Lee H. S., Ha C. S. and Kim C. Y. (2007). Hematological and Blood Biochemical Values of Laboratory Beagle Dogs. Lab. Anim. Res. 23 (3), 223-229
  4. Kang B. K., Chon S. K., Kim S. H., Jeong S. Y., Kim M. S., Cho S. H., Lee H. B. and Khang G. (2004). Controlled release of paclitaxel from microemulsion containing PLGA and evaluation of anti-tumor activity in vitro and in vivo. Int. J. Pharm. 286(1-2), 147-56
  5. Konno T., Watanabe J. and Ishihara K. J. (2003). Enhanced solubility of paclitaxel using water-soluble and biocompatible 2-methacryloyloxyethyl phosphorylcholine polymers. Biomed. Mater. Res. 65(2), 209-14
  6. Le Garrec D., Gori S., Luo L., Lessard D., Smith D. C., Yessine M. A., Ranger M. and Leroux J. C. (2004). Poly (N-vinylpyrrolidone)-block-poly(D,L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation. J. Control Release. 99(1), 83-101
  7. Lee S. Y. (2002). Pharmacokinetics of the Paclitaxel of New Micelle Formulation. Ewha Womans University., Seoul, Korea
  8. Loos W. J., Szebeni J., ten Tije A. J., Verweij J., van Zomeren D. M., Chung K. N., Nooter K., Stoter G. and Sparreboom A. (2002). Preclinical evaluation of alternative pharmaceutical delivery vehicles for paclitaxel. Anticancer Drugs. 13(7), 767-75
  9. Mielke S., Sparreboom A. and Mross K. (2006). Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes. Eur. J. Cancer. 42(1), 24-30
  10. Nuijen B., Bouma M., Schellens J. H. and Beijnen J. H. (2001). Progress in the development of alternative pharmaceutical formulations of taxanes. Invest. New Drugs. 19(2), 143-53
  11. Shimomura T., Fujiwara H., Ikawa S., Kigawa J. and Terakawa N. (1998). Effects of Taxol on blood cells. Lancet. 352(9127), 541-2
  12. Singla A. K., Garg A. and Aggarwal D. (2002). Paclitaxel and its formulations. Int. J. Pharm. 235(1-2), 179-92
  13. Sparreboom A., van Zuylen L., Brouwer E., Loos W. J., de Bruijn P., Gelderblom H., Pillay M., Nooter K., Stoter G., and Ver weij J. (1999). Cremophor EL-mediated Alteration of Paclitaxel Distribution in Human Blood: Clinical Pharmacokinetic Implications. Cancer Res. 59: 1454-1457
  14. Szebeni J. (2005). Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology. 216(2-3): 106-21
  15. van Zuylen L., Verweij J., Sparreboom A. (2001a). Role of formulation vehicles in taxane pharmacology. Invest New Drugs. 19(2):125-41
  16. van Zuylen L., Karlsson M. O., Verweij J., Brouwer E., de Bruijn P., Nooter K., Stoter G. and Sparreboom A. (2001b). Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles. Cancer Chemother. Pharmacol. 47(4), 309-18
  17. Weiss R. B., Donehower R. C., Wiernik P. H., Ohnuma T., Gralla R. J., Trump D. L., Baker J. R. Jr., Van Echo D. A., Von Hoff D. D. and Leyland-Jones B. (1990). Hypersensitivity reactions from taxol. J. Clin. Oncol. 8(7), 1263-8

Cited by

  1. Intratumoral delivery of paclitaxel using a thermosensitive hydrogel in human tumor xenografts vol.36, pp.1, 2013,