Validated high-performance liquid chromatographic assay for simultaneous determination of dacarbazine and the plasma metabolites 5-(3-hydroxymethyl-3-methyl-1-triazeno)imidazole-4-carboxamide and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide |
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| Institution: | 1. Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan;2. R&D Lab, Nano Dex Inc., Kanagawa 243-0435, Japan;1. Quantitative Proteomics Center and Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;2. Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan;3. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan;4. Department of Genome Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;5. Physiology Biophysics and Systems Biology Program, Weill Graduate School of Medical Sciences, Cornell University, NY 10065, USA;6. Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan;7. Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan;1. Division of Endocrinology, Central Drug Research Institute, (CSIR-CDRI), Lucknow 226031, India;2. Division of Pharmaceutics, Central Drug Research Institute, (CSIR-CDRI), Lucknow 226031, India;1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;2. Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan;3. Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States |
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| Abstract: | Dacarbazine (DTIC) is a prodrug that is clinically effective in the treatment of Hodgkin’s disease, melanoma and soft tissue sarcoma. To better characterize the clinical pharmacology of parent drug and reactive metabolites, a reversed-phase HPLC method with UV detection was developed for simultaneous determination of dacarbazine and the metabolites 5-(3-hydroxymethyl-3-methyl-1-triazeno)imidazole-4-carboxamide (HMMTIC) and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC). Chromatographic separation was achieved with a Zorbax SB-CN column and with a mobile phase of 80% 50 mM ammonium phosphate, pH 6.5, 20% methanol and 0.1% triethylamine. HMMTIC, MTIC and DTIC were extracted from plasma with methanol precipitation of the proteins. Recovery of DTIC and the metabolites from whole blood was greater than 92%. Rapid processing of whole blood, methanol extraction and storage at ?70°C substantially increased the stability of HMMTIC and MTIC from less than 15 min to 3 days. Precision for HMMTIC, MTIC and DTIC ranged from 3.7 to 16.3% relative standard deviation. The accuracy ranged from 101 to 114% for all three analytes. The validated assay was used to determine the pharmacokinetic data for dacarbazine and its active metabolites for human patients with recurrent glioma receiving DTIC intravenously. |
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