Radioimmunoassay and Preliminary Pharmacokinetic Studies in Rats of 5′-Noranhydrovinblastine (Navelbine)¹

The antitumor drug navelbine (5′-noranhydrovinblastine) was converted into a reactive acid azide and covalently coupled to free amino groups of bovine serum albumin. The conjugate was used to raise specific antibodies in rabbits. The acid azide derivative was also reacted with the peptide glycyl-l-tyrosine, and the conjugate was radiolabeled with ¹²⁵I. The resulting high-specific-activity γ-emitting probe was shown to bind very tightly to anti-navelbine antiserum. Using these reagents, a radioimmunoassay was developed which proved sensitive enough to measure less than 10 fmol of navelbine in serum and which showed little cross-reaction with closely related analogues such as vinblastine, vindesine, or 5′-6′-secovinblastine. A preliminary pharmacokinetic analysis was performed in rats given navelbine i.v. (dose, 1.2 mg/kg). The radioimmunoassay was used to monitor the plasma concentration decay kinetics after injection. Navelbine systemic clearance was estimated from the area under the concentration-time curves [1.9 ± 0.5 (S.D.) liters/hr/kg] and was found to be larger than that of vinblastine (1.1 ± 0.4 liters/hr/kg) measured under similar conditions (dose, 0.6 mg/kg). Terminal half-lives were 8.9 ± 2.1 hr for navelbine and 8.1 ± 2.6 hr for vinblastine. This radioimmunoassay will provide a sensitive method with which to monitor plasma levels of navelbine during clinical trials and to further study the relationships between pharmacokinetics, toxicity, and antitumor activity among Vinca alkaloids.