The overall objective of this proposal in to study the metabolism of taxol in humans. Although taxol in undergoing broad clinical trials based on its novel mechanism of action and unique preclinical and clinical antineoplastic activities, there is virtually no information available pertaining to the human metabolism and pharmacologic disposition of taxol and related agents. In fact, the disposition of only 5-10% of infused drug has been accounted for in previous studies. This proposal is a collaborative effort on behalf of investigators at JHOC who have considerable experience in taxol's cellular biology, clinical pharmacology and development, and investigators at RTI who originally identified taxol and have expertise in the metabolism, chemistry, and synthesis of complex antineoplastins as well as other compounds. This proposal seeks to identify the chemical structures of the human metabolites of taxol, define the mechanisms and routes of metabolism and disposition, model the dynamic kinetics of taxol and metabolites, determine the activity of metabolites with respect to tubulin polymerization, cytotoxicity (tumor and hematopoietic cells), and effects on microtubule morphology and cell cycle traverse. To accomplish these goals, tritium- and deuterium-labeled taxol will be synthesized. Blood, urine, feces, and bile will be collected 'from patients receiving taxol containing tracer doses of radiolabeled drug. In vitro metabolic studies using P-450 homogenates from induced animal livers will compliment these efforts. Next, metabolite identification will be accomplished by various analytical methods, and metabolites will then be purified from these sources as well as from tissue samples from patients receiving unlabeled taxol. Following identification, quantification, and purification of metabolites, the dynamic kinetics of taxol and metabolites will be described and pertinent biological effects will be determined. As well as defining the metabolism of a potential widely used anticancer agent, metabolic information may permit interindividual dose optimization, biochemical modulation to maximize exposure to active metabolites while minimizing exposure to toxic metabolites to achieve an optimal therapeutic ratio and conservation of limited drug supplies. Identifying active metabolites with less complex structures and more favorable solubility characteristics may also redirect efforts towards more feasible syntheses and use of less toxic clinical formulations.
| Monsarrat, B; Alvinerie, P; Wright, M et al. (1993) Hepatic metabolism and biliary excretion of Taxol in rats and humans. J Natl Cancer Inst Monogr :39-46 |
