title: Disposition of the monoclonal antibody-vinca alkaloid conjugate, KS1/4-DAVLB (LY256787), in Fischer 344 rats and rhesus monkeys.
abstract: The conjugate, KS1/4-DAVLB, of the murine monoclonal antibody KS1/4 with the vinca alkaloid 4-desacetylvinblastine (DAVLB) was administered intravenously to rats and monkeys. Terminal plasma half-life (t1/2) values were measured as radioequivalents and as functionally immunoreactive antibody conjugate after dosing with KS1/4-[3H]DAVLB. The t1/2 values, determined radiometrically, were 145 hr and 62 hr in male rats after 10 and 100 mg/kg doses and 92 hr and 90 hr in male and female monkeys after a 40 mg/kg dose. Comparable results were obtained when the functionally immunoreactive conjugate concentrations were determined by an enzyme-linked immunosorbent assay technique. The ratio of 35S:3H in the plasma after dosing rats with 100 mg/kg [35S]KS 1/4-[3H]DAVLB remained reasonably constant during 336 hr. Less than 1% of the total vinca alkaloid equivalents present in the plasma at any time could be extracted as free vinca species; the major vinca alkaloid metabolities present at early time points were hemisuccinate derivatives of DAVLB, whereas, at later times, DAVLB and its N-oxide were equally as concentrated. The major pathway of elimination was fecal with about one-half of the administered radioactivity cleared in 150-250 hr. After dosing with [35S]KS 1/4-[3H]DAVLB, the ratio of 35S:3H radioactivity in the bile was substantially less than that in the plasma. Evaluation of radioactivity eluted from the bile by size-exclusion HPLC showed that almost all of the tritium was associated with material of lower molecular weight than that of KS 1/4-DAVLB.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D000922:Immunotoxins; D008251:Macaca / Q000378:metabolism*; D008253:Macaca mulatta / Q000378:metabolism*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344 / Q000378:metabolism*; D011919:Rats, Inbred Strains / Q000378:metabolism*; D012016:Reference Values; D014018:Tissue Distribution; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C052417:4-desacetylvinblastine-monoclonal antibody KS1-4 conjugate; D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D014747:Vinblastine