title: An HPLC assay utilizing solid-phase extraction for CI-1010, an alkylating radiosensitizer, in rat plasma.
abstract: 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 < or = 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 micrograms 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 < or = 3.27%, respectively, and +/- 12.8 and < or = 4.06%, respectively, for quality controls containing nominal concentrations of 0.400, 4.00 and 40.0 micrograms 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 146415 and PD 146923 were both stable in rat plasma at 4 degrees C and -77 degrees C for at least 7 h and 154 days, respectively. CI-1010 was not stable in rat plasma at 4 degrees C. CI-1010, PD 146415 and PD 126675 were stable for at least 63 days in 10 mM phosphate buffer at pH 3.0 and 4 degrees C. Under identical conditions PD 146923 was stable for only 8 days. The applicability of this method to determine concentrations of PD 146415 and PD 146923 in rat plasma is reported in this paper.
authors.affiliation: Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105, USA. BullenW@aa.wl.com
authors.forename: W W
authors.initials: WW
authors.lastname: Bullen
authors.forename: D T
authors.initials: DT
authors.lastname: Rossi
authors.forename: K L
authors.initials: KL
authors.lastname: Hoffman
authors.forename: A
authors.initials: A
authors.lastname: Suri
authors.forename: C D
authors.initials: CD
authors.lastname: Lathia
mesh_terms: D000477:Alkylating Agents / Q000032:analysis*; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods; D004355:Drug Stability; D007275:Injections, Intravenous; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000032:analysis* / Q000097:blood* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics; D011838:Radiation-Sensitizing Agents / Q000032:analysis*; D051381:Rats; D015203:Reproducibility of Results; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000477:Alkylating Agents; D009593:Nitroimidazoles; C111723:PD 146415; C105890:PD 146923; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; C067834:RB 6145