Determination of tissue concentrations of vinca alkaloids by radioimmunoassay.

Methodology for the determination of tissue concentrations of the vinca alkaloids has been developed with a specific radioimmunoassay (RIA). Data obtained with this RIA were compared with those obtained following direct administration of radiolabeled vinblastine. Distribution of radiolabeled vinblastine was also compared between control rats and those bearing the transplantable tumor Lymphoma 8. Vindesine concentrations in various rat tissues were determined via RIA over a 52-hr period.

Correlation of cytotoxicity and mitotic spindle dissolution by vinblastine in mammalian cells.

In two hamster cell lines that differed 100-fold in their vinblastine sensitivity, dissolution of the mitotic spindle by vinblastine in living cells correlated with cytotoxicity from vinblastine expressed as suppression of colony formation. The effect on the spindle apparatus occurred in 30 sec or less and thus provides a rapid assay for determining the cytotoxic effects of the Vinca alkaloids, as well as the potential for quantitative assay of solutions of Vinca derivatives.

Pharmacokinetics and metabolism of vinblastine in humans.

The pharmacokinetics of vinblastine in humans was examined using a radioimmunoassay specific for both the Vinca alkaloids and aromatic ring [3H]vinblastine. The data were consistent with a three-compartment open model system with the following values, alpha phase: t1/2=3.90+/-1.46 min; Vc=16.8+/-7.1 liters. beta phase:t1/2=53.0+/-13.0 min; Vbeta=79.0+/-52.0 liters; gamma phase:t1/2=1173.0+/-65.0 min; Vgamma=1656.0+/-717.0 liters. Most significant was the finding that vinblastine is metabolized to deacetylvinblastine and that this compound is more biologically active on a weight basis than the parent. No other biologically active metabolites appeared to be present in urine or in stool.

Pharmacokinetics of vindesine and vincristine in humans.

Vindesine, a new Phase 1 Vinca alkaloid congener, exhibited serum pharmacokinetic behavior in humans compatible with a three-compartment, open mammilary model. The kinetic parameters included: t1/2 alpha=3.24+/-1.14 min, t1/2beta=99.0+/-44.5 min, t1/2gamma=1213+/-493 min, Vc (Valpha)=4.81+/-2.12 liters, Vbeta=58.2+/-50.5 liters, Vgamma=598+/-294 liters. Vincristine, studied only for the first 4 hr, behaved like a two-compartment system, with values of t1/2 alpha=3.37+/-0.72 min, t1/2beta=155+/-18 min, Valpha=4.53+/-0.49 liters, and Vbeta=57.3+/-21.1 liters. Urine excretion data demonstrated that most drug elimination occurred within the first 24 hr and amounted to 13.2+/-5.9% for vindesine and 9.5+/-5.1% for vincristine.

Endodermal sinus tumor. Report of a case with remission following chemotherapy.

The case of a 33-year-old white female with an endodermal sinus tumor of the ovary who manifested remission of her disease as a result of the intermittent administration of chlorambucil is described. This remission following chemotherapy with a single alkylating agent is unusual.

Inhibition of tubulin-microtubule polymerization by drugs of the Vinca alkaloid class.

A series of Vinca alkaloids were found to block polymerization of crude tubulin extracts of porcine brain in a dose-dependent manner. This appears to be a specific effect occurring at low concentrations of drug. The concentration of vinblastine that prevents polymerization by 50% was 4.3 x 10(-7) mole/liter for a tubulin concentration of 3.0 mg/ml, and this concentration is consistent with levels achieved in vivo following routine pharmacological doses in humans.

The pharmacokinetics of 4-acetyl tritium vinblastine in two patients.

Vinblastine, labeled with tritium in the 4-acetyl group, was given to two patients with malignant disease, and the pharmacokinetic behavior of the drug was determined. Clearance of radioactivity from the blood was biphasic, with t1/2 values for a first rapid phase of 4.25 and 4.78 min, and for a slower phase of 185 and 195 min. The volume of the central compartment was calculated as 29.7 and 39.4 liters, while the total fictive volume of distribution was 86.4 and 111.4 liters. Binding to blood components occurred in the order: plasma greater than platelets greater than red blood cells greater than white blood cells. Excretion of radiolabel occurred via the stool and the urine so that, after 72 hr, 25 and 41% of the total dose had appeared in the former and 19 a nd 23% had appeared in the latter. Appreciable amounts of unchanged drug appeared in the urine, while very little appeared in the stool, suggesting hepatic metabolism, consistent with prior animal studies.