High-performance liquid chromatographic assay for CI-980, a novel 1-deaza-7,8-dihydropteridine anticancer agent, in human plasma and urine

CI-980, a 1-deaza-7,8-dihydropteridine, is a novel anticancer agent that is a potent mitotic inhibitor acting as a tubulin binder similar to the vinca alkaloids. CI-980 has shown equivalent or superior anticancer activity in vitro compared to vincristine and retains full activity against vincristine...

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Published in:Journal of chromatography. B, Biomedical applications Biomedical applications, 1995-06, Vol.668 (1), p.141-151
Main Authors: Bullen, William W., Whitfield, Lloyd R., Walter, Gary A., Brodfuehrer, Joanne I.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - blood
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - urine
Carbamates - blood
Carbamates - pharmacokinetics
Carbamates - urine
Chromatography, High Pressure Liquid - methods
Drug Stability
Freezing
Humans
Pyrazines - blood
Pyrazines - pharmacokinetics
Pyrazines - urine
Pyridines - blood
Pyridines - pharmacokinetics
Pyridines - urine
Reproducibility of Results
Spectrometry, Fluorescence
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Summary:CI-980, a 1-deaza-7,8-dihydropteridine, is a novel anticancer agent that is a potent mitotic inhibitor acting as a tubulin binder similar to the vinca alkaloids. CI-980 has shown equivalent or superior anticancer activity in vitro compared to vincristine and retains full activity against vincristine resistant tumors in vitro. A high-performance liquid chromatographic (HPLC) assay was developed and validated for human plasma and urine to support Phase 1 clinical trials. CI-980 and PD 080658, internal standard, were isolated from 2-ml samples of human plasma and urine by solid-phase extraction with Bond-Elut C 18 cartridges. Urine samples must be pretreated with bovine serum albumin (BSA) to minimize the binding of CI-980 to glass and some plastics. The eluate from the cartridges for both matrices was evaporated to dryness and taken up in mobile phase. Zorbax RX C 18 columns, mobile phase buffer of 10 m M ammonium dihydrogen phosphate at pH 7.5 and a flow--rate of 0.75 ml/min were used for both matrices. Column dimensions, column temperature and mobile phase acetonitrile-buffer ratio were 300 mm × 4.6 mm I.D., 30°C and 38:62 (v/v), respectively, for the plasma assay and 250 mm × 4.6 mm I.D., 35°C and 40:60 (v/v), respectively, for the urine assay. Column effluent was monitored fluorometrically for the plasma method using excitation and emission wavelengths of 388 nm and 473 nm, respectively. Ultraviolet detection at 380 nm was used for the urine method. Peak-area ratios were proportional to CI-980 concentrations from 0.2 to 25 ng/ml and 1 to 100 ng/ml for plasma and urine, respectively. CI-980 in water will bind to glass and plastics but not PTFE or stainless steel. Urine calibration standards were frozen prior to use in order to compensate for loss of CI-980 due to freezing in this matrix. The accuracy of the assay was within 4.7%, with a precision of 5.6% for both matrices. Recoveries ranged from 93.8 to 102% and 90.7 to 92.3% for plasma and urine, respectively. CI-980 was stable in plasma and urine for at least 275 and 217 days, respectively, when stored at −70°C. The assay is suitable for studying the clinical pharmacokinetics of CI-980.
ISSN:0378-4347
1572-6495
DOI:10.1016/0378-4347(95)00067-S