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

Laboratoire de Pharmacocinétique, INSERM SC n° 16, Faculté de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5 [R. R., J-P. C.]; Groupe de Recherche en Immunologie et Pharmacologie des Anti-Cancéreux, Institut Paoli Calmettes, 232 Boulevard de Sainte Marguerite, 13273 Marseille Cedex 9 [M. M.]; and Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, Case 906, 13288 Marseille Cedex 9 [J. B.], France

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 -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.

¹ This work was supported by institutional grants from Institut National de la Santé et de la Recherche Medicale and Centre National de la Recherche Scientifique.

² To whom requests for reprints should be addressed. Present address: Laboratory of Mathematical Biology, Bldg. 10, Room 4B56, National Cancer Institute, NIH, Bethesda, MD 20205.

Received 11/ 3/82. Accepted 8/30/84.

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