Evidence for the Conversion of Docetaxel into 7-Epidocetaxel in Patients Receiving Conventional Taxotere® Based Chemotherapy

• Martin Czejka

  Division of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria

• Ernst Ulsperger

  Hospital Hietzing, 5th Medical Department / Oncology, A-1130 Vienna, Austria

• Heinz Schnait

  Ebewe Pharma, A-4866 Unterach / Attersee, Austria

• Tamara Brumnik

  Division of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria

• Joerg Schierholz

  Ebewe Pharma, A-4866 Unterach / Attersee, Austria

• Philipp Buchner

  Division of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria

• Richard Greil

  State Hospital Salzburg, III. Department for Internal Medicine, A-5020 Salzburg, Austria

 Purpose:Epimerization at the C7atom of the baccatin moiety is a common in-vitro pathway for all taxanes, including the natural precursor 10-deacetyl baccatin III and the antineoplastic drugs paclitaxel and docetaxel. To date this in-vitro epimerization of both drugs has been elucidated completely, but epimerization of docetaxel in patients during chemotherapy has not yet described. The goal of this study was to identify the epimer of docetaxel in plasma and urine of taxotere treated patients.

Patients and Methods:12 patients suffering from mamma carcinoma, lung cancer or prostate cancer were treated with various docetaxel-based schedules. Blood samples were drawn before start of infusion, at the end of infusion and 20 min thereafter, urine was collected and pooled for 6 hours. Docetaxel and its epimer epidocetaxel were quantified by solid phase extraction and reversed phase HPLC.

Results:In 8 of 12 patients epidocetaxel could be quantified in plasma at the end of infusion (range 0.05 - 0.54 µg/ml). 20 minutes later concentrations were below LOQ due to rapid distribution of docetaxel into tissue. In urine, epidocetaxel has been found in 7 of 12 patients (range 0.1 - 0.5 µg/ml).

Conclusion: Epidocetaxel is a distinct docetaxel metabolite in man. So our knowledge, this is the first time that quantification of epidocetaxel in blood and urine of chemotherapy patients has been reported. This finding is important for designing of new docetaxel generic drugs and the development of new chemotherapeutic schedules using docetaxel. To date the in-vivo pharmacologic and toxic properties of the epimer remain unclear.

Food and Drug Administration, National Cancer Institute [monograph at the internet] 2013: Available from: www.cancer.gov/cancertopic/druginfo/docetaxel

Bruno R, Sanderink GJ. Pharmacokinetics and metabolism of taxotere (docetaxel). Cancer Surv 1993; 17: 305-13

Shou M, Martinet M, Korzekwa KR. Role of human cytochrome P450 3A4 and 3A5 in the metabolism of taxotere and its derivatives: enzyme specificity, interindividual distribution and metabolic contribution in human liver. Pharmacogenetics 1998; 8: 391-401. http://dx.doi.org/10.1097/00008571-199810000-00004

Gaillard C, Monserrat B, Vuilhorgne MI. Docetaxel (taxotere) metabolism in the rat in vivo and in vitro. Proc Am Assoc Cancer Res 1994; 35: 428.

Vejpongsa P, Yeh ETH. Topoisomerase 2β: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity. Clin Pharmacol Therapeut 2014; 95: 45-52. http://dx.doi.org/10.1038/clpt.2013.201

Forrest RA, Swift LP, Evison BJ, et al. The hydroxy epimer of doxorubicin controls the rate of formation of cytotoxic anthracycline-DNA adducts. Cancer Chemother Pharmacol 2013; 71: 809-16. http://dx.doi.org/10.1007/s00280-012-2049-x

Tian J, Stella VJ. Degradation of paclitaxel and related compounds in aqueous solutions I: epimerization. J Pharm Sci 2008; 97: 3100-8. http://dx.doi.org/10.1002/jps.21214

Kumar D, Tomar RS, Deolia SK. Isolation and characterization of degradation impurities in docetaxel drug substance and its formulation. J Pharm Biomed Analysis 2007; 43: 1228-35. http://dx.doi.org/10.1016/j.jpba.2006.10.015

Dev RV, Babu JM, Vyas, Ram K, et al. Isolation and characterization of impurities in docetaxel. J Pharm Biomed Analysis 2006; 40: 614-22. http://dx.doi.org/10.1016/j.jpba.2005.10.037

Mukund Keshav Gurjar, inventor; Emcure Pharmaceutical Limited. An improved process for preparation of taxane derivatives. European Patent Application No: 10014181.1. 2010 Nov.

Ringel I, Horwitz SB. Taxol is converted to 7-epitaxol, a biologically active isomer in cell culture. J Pharmacol Exper Therapeut 1987; 242: 692-98.

Ringel I, Horwitz SB. Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst 1991; 83: 288-91. http://dx.doi.org/10.1093/jnci/83.4.288

Bournique B, Lemarié A. Docetaxel (taxotere) is not metabolized by recombinant human CYP1B1 in vitro, but acts as an effector for this isozyme. Drug Metab Disp 2002; 30: 1149-52. http://dx.doi.org/10.1124/dmd.30.11.1149

Royer I, Alvinerie P, Armand JP. Paclitaxel metabolites in human plasma and urine: identification of 6α-hydroxytaxol, 7-epitaxol and taxol hydrolysis products using liquid chromatography / atmospheric-pressure chemical ionization mass spectrometry. Rapid Commun Mass Spectrometry 1995; 9: 495-502. http://dx.doi.org/10.1002/rcm.1290090605

Vaclavikova R, Soucek P, Svobodova L Anzenbacher P, Simek, Guengerich FP, Gut I. Different in-vitro metabolism of paclitaxel and docetaxel in humans, rats, pigs and minipigs. Drug Metab Dispos 2004; 32: 66. http://dx.doi.org/10.1124/dmd.32.6.666

Mohsin S, Arellano IH, Choudhury NR, Garg S. Docetaxel epimerization in silicone films: a case of drug excipient incompatibility. Drug Test Analysis 2014. http://dx.doi.org/10.1002/dta.1617

Furtlehner A, Schueller J, Jarisch I, Ostermann E, Czejka M. Disposition of paclitaxel (Taxol®) and its metabolites in patients with advanced breast cancer (ABC) when combined with trastuzumab (Herceptin®). Eur J Drug Metab Pharmacokin 2005; 30: 145-50. http://www.biomedcentral.com/1472-6904/6/2/-ins1

Bruno R, Hille D, Riva A, et al. Population pharmacokinetics - pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 1998; 16: 187-96.

Sparreboom A, Van Tellingen O, Scherrenburg EJ. Isolation, purification and biological activity of major docetaxel metabolites from human faeces. Drug Met Dispos 1996; 24: 655-58.

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