An HPLC assay utilizing solid-phase extraction for CI-1010, an alkylating radiosensitizer, in rat plasma

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 16; no. 1; pp. 47 - 55
• Main Authors: Bullen, William W., Rossi, David T., Hoffman, Keith L., Suri, Ajit, Lathia, Chetan D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.09.1997; Elsevier Science
• Subjects: 2-nitroimidazoles; Alkylating Agents - analysis; Alkylating radiosensitizer; Analysis; Animals; Biological and medical sciences; Chromatography, Liquid - methods; CI-1010; Drug Stability; General pharmacology; HPLC; Injections, Intravenous; Medical sciences; Nitroimidazoles - administration & dosage; Nitroimidazoles - analysis; Nitroimidazoles - blood; Nitroimidazoles - pharmacokinetics; PD 146415; PD 146923; Pharmacology. Drug treatments; Prodrugs - administration & dosage; Prodrugs - analysis; Prodrugs - pharmacokinetics; Radiation-Sensitizing Agents - analysis; Rat plasma; Rats; RB 6145; Reproducibility of Results; RSU 1069; Solid-phase extraction; Spectrophotometry, Ultraviolet; CI-1010; RSU 1069; Alkylating radiosensitizer; RB 6145; PD 146415; 2-nitroimidazoles; PD 146923; Solid-phase extraction; HPLC; Rat plasma; Validation; Nitro compound; Solid phase extraction; Imidazole derivatives; Biological fluid; Rat; Metabolite; Rodentia; HPLC chromatography; Liquid chromatography; Prodrug; Metabolism; Blood plasma; Vertebrata; Mammalia; Ultraviolet detector; Radiosensitizing agent; Animal; Quality control; Quantitative analysis
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/S0731-7085(97)00013-7

CI-1010, a 2-nitroimidazole, is a chiral prodrug for the active moiety PD 146923 and is under development as an alkylating radiosensitizer to be used as an adjuvant to radiotherapy. Because CI-1010 has an estimated half-life ≤ 2 min under physiological conditions its metabolites/degradation products PD 146415, an inactive moiety, and PD 146923 were assayed to support rat toxicology studies. The method involves the processing of plasma samples through phenyl solid-phase extraction cartridges followed by chromatography on CN columns with UV detection at 325 nm. The assay appears linear over the range 0.050–100 μg ml −1 for both PD 146415 and PD 146923. Interrun accuracy and precision estimates for PD 146415 and PD 146923 were within ± 6.50 and ≤ 3.27%, respectively, and ± 12.8 and ≤ 4.06%, respectively, for quality controls containing nominal concentrations of 0.400, 4.00 and 40.0 μg ml −1. The absolute recovery of CI-1010, PD 146415 and internal standard, PD 126675, were approximately 40, 96 and 95%, respectively. The recovery of PD 146923 appeared concentration dependent and ranged from 68 to 92%. PD 146145 and PD 146923 were both stable in rat plasma at 4°C and − 77°C for at least 7 h and 154 days, respectively. CI-1010 was not stable in rat plasma at 4°C. CI-1010, PD 146145 and PD 126675 were stable for at least 63 days in 10 mM phosphate buffer at pH 3.0 and 4°C. Under identical conditions PD 146923 was stable for only 8 days. The applicability of this method to determine concentrations of PD 146145 and PD 146923 in rat plasma is reported in this paper.