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A sensitive and specific radioimmunoassay for LY309887, a potent inhibitor of glycinamide ribonucleotide formyltransferase.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 1998 Jan; Vol. 4 (1), pp. 157-63. - Publication Year :
- 1998
-
Abstract
- LY309887, a reduced analogue of folic acid, is a potent inhibitor of glycinamide ribonucleotide formyltransferase and possesses a broad spectrum of antitumor activity. During preclinical studies using supplementation with oral folic acid, this second-generation inhibitor displayed both the desired safety profile and the pharmacology to warrant clinical investigation. A sensitive analytical method was needed to assess the pharmacokinetics of LY309887 due to the low doses planned for Phase I studies and the potential for low concentrations in plasma long after i.v. administration. We therefore undertook the development of a competitive RIA. A highly specific antiserum was raised in rabbits following immunization with LY309887 coupled to BSA. A RIA tracer was prepared by radioiodination of compound 389753, the adduct of LY309887 with p-tyramine. We developed a competitive-binding RIA procedure and used superparamagnetic particles coated with goat antirabbit IgG as a method for separating the bound and free forms of LY309887. The RIA is sensitive (0.5 ng/ml in serum and 25 ng/ml in urine), specific (negligible interference from endogenous folates), and reproducible (interassay coefficients of variation ranging from 8.1 to 15.4% and 7.6 to 8.3% for serum and urine controls, respectively). We used the RIA to assess the i.v. pharmacokinetics of LY309887 in both patients with metastatic cancer and dogs. The sensitivity of the RIA permitted the demonstration that serum concentrations of LY309887 decline in a multiexponential manner with a prolonged terminal elimination phase. We conclude that the RIA is a valid method for quantifying LY309887 in biological fluids.
- Subjects :
- Animals
Dogs
Female
Humans
Immune Sera immunology
Phosphoribosylglycinamide Formyltransferase
Rabbits
Radioimmunoassay
Sensitivity and Specificity
Tetrahydrofolates immunology
Tetrahydrofolates pharmacokinetics
Antineoplastic Agents analysis
Enzyme Inhibitors analysis
Hydroxymethyl and Formyl Transferases antagonists & inhibitors
Tetrahydrofolates analysis
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 4
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 9516965