Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers.
Fialuridine (FIAU) is a halogen-substituted analog of thymidine that was undergoing clinical investigation as a drug for the treatment of chronic hepatitis B viral infection. However, clinical trials of FIAU were terminated after adverse events occurred following chronic oral administration. Prior to the termination of clinical trials, a sensitive assay was needed for the measurement of FIAU because of the anticipated low dose administered to patients. We therefore undertook the development of a radioimmunoassay (RIA). A specific antiserum was raised in rabbits following immunization with a 5'-O-hemisuccinate analog of FIAU coupled to keyhole limpet hemocyanin. Radiolabeled FIAU was synthesized by a destannylation procedure by using sodium [125I]iodide. We developed a competitive-binding procedure and used precipitation with polyethylene glycol as the method for separating the bound and free forms of FIAU. The RIA is sensitive (0.2 ng/ml), specific (negligible interference from known metabolites and endogenous nucleosides), and reproducible (interassay coefficients of variation range from 5 to 19.7% for serum controls). We used the RIA to assess the pharmacokinetics of FIAU in healthy adult volunteers following administration of a single 5-mg oral dose. The sensitivity of the RIA permitted the detection of a prolonged elimination phase for FIAU in healthy volunteers and dogs, with mean elimination half-lives of 29.3 and 35.3 h, respectively. We conclude the RIA is a valid method for the quantification of FIAU in biological fluids.
Bowsher
R R
RR
Department of Drug Disposition & Bioanalytical Research, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana.
Compton
J A
JA
Kirkwood
J A
JA
Place
G D
GD
Jones
C D
CD
Mabry
T E
TE
Hyslop
D L
DL
Hatcher
B L
BL
DeSante
K A
KA
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000032:analysis* / Q000493:pharmacokinetics*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001682:Biological Availability; D004334:Drug Administration Schedule; D005215:Fasting; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008875:Middle Aged; D011817:Rabbits; D011863:Radioimmunoassay / Q000379:methods; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D000998:Antiviral Agents; D007457:Iodine Radioisotopes; D001086:Arabinofuranosyluracil; C043457:fialuridine