Vincristine disposition in children with acute lymphoblastic leukemia.

Vincristine (VCR) has been widely used to treat childhood malignancies for over thirty years, but its plasma disposition has not yet been well-defined. Therefore, we conducted a pharmacokinetic study of VCR in 17 children with acute lymphoblastic leukemia (ALL) receiving the first dose of VCR. A new high-performance liquid chromatographic assay was used for the measurement of VCR in plasma. A two-compartment pharmacokinetic model was fit to the data by nonlinear least-squares regression. Estimated pharmacokinetic parameters were highly variable; mean (S.D.) volume of distribution at steady-state was 360 (176) L.m-2; total body clearance was 431 (238) ml.min-1.m-2, and elimination half-life was 823 (390) min. These results were compared to data from eight adults with lung cancer. Mean volume of distribution in adults and children were similar, but VCR clearance was significantly larger in children (P = 0.01), resulting in a significantly longer elimination half-life in the adults (P < 0.01). We conclude that administration of a standard dosage of VCR to children with ALL results in a highly variable systemic drug exposure, which may have implications for the oncolytic effect and/or toxicity in individual patients. Comparison of data from children and adults suggests that VCR elimination rate is a function of age; this could account for more severe neurotoxicity in older patients. However, it cannot be excluded that differences between the children and adults may be due to other variables than age. Future studies should focus on the possible influence of multidrug resistance modulating agents on VCR pharmacokinetics and on pharmacokinetic-pharmacodynamic relationships in individual patients.

Sensitive method for the determination of vincristine in human serum by high-performance liquid chromatography after on-line column-extraction.

A column-switching high-performance liquid chromatographic method was developed for the determination of vincristine in serum. Sample preparation was carried out by means of on-line column-extraction, using a C18 reversed-phase preconcentration column. This technique is simple (minimizing manual sampling errors), rapid (reduction of time and costs) and can be easily automated. Both ultraviolet and electrochemical detection are possible, but the latter shows a cleaner chromatogram and is, by the use of a new electrochemical detector, far more sensitive (detection limit 0.3 microgram/l at a signal-to-noise ratio of 3). A matrix study was carried out (using human serum and urine and two kinds of calf's serum). Although it appeared that the system was matrix-dependent, no difference in matrix effects could be found in the serum or plasma of different patients. Controls for human serum analysis should be prepared in human serum. With the method described, pharmacokinetic studies of vincristine in children can be performed.

Stability of vinca alkaloid anticancer drugs in three commonly used infusion fluids.

The chemical stabilities of the vinca alkaloid anticancer drugs vinblastine, vincristine, and vindesine have been studied in three commonly used infusion fluids at 4 and 25 degrees C. The infusion fluids were: 0.9% sodium chloride, 5% dextrose, and Ringer's Lactate injection. Stability has been measured by using a stability-indicating high performance liquid chromatographic assay with ultraviolet detection. At 4 degrees C no significant degradation of the vinca alkaloids occurred within a storage period of three weeks. The stability tests at 25 degrees C also revealed that vinblastine, vincristine, and vindesine are stable (greater than 95% remained) when stored for three weeks at this temperature in 5% dextrose, 0.9% sodium chloride, or Ringer's Lactate infusion fluids.

Determination of vinca alkaloids in plasma and urine using ion-exchange chromatography on silica gel and fluorescence detection.

The development of a method for the determination of the antineoplastic vinca alkaloids vinblastine and vindesine in biological samples is described. The selectivity of the assay is high owing to the use of solid-phase extraction on a cyanopropyl extraction column prior to isocratic chromatography on unmodified silica gel with fluorescence detection. The influence of acetonitrile concentration and mobile phase pH on the capacity factors of the drugs was studied in order to optimize the separation between the drugs and endogenous components. The effect of varying the type and concentration of competing cations in the mobile phase was also examined. The limit of determination (signal-to-noise ratio = 3) for vinblastine is 0.5 ng/ml in plasma and urine and for vindesine 2.5 ng/ml. The assay is suitable for determining the concentrations of both compounds in plasma and urine samples from patients.

Analysis of vinca alkaloids in plasma and urine using high-performance liquid chromatography with electrochemical detection.

The reversed-phase high-performance liquid chromatography with electrochemical detection was used to quantify plasma and urine levels of vinblastine, vincristine, vindesine and a metabolite of vinblastine, desacetylvinblastine. Sample clean-up consisted of solid-phase extraction with a Bond Elut CN column. The extracts were separated on a Hypersil ODS column. The mobile phase consisted of a mixture of methanol and 10 mM phosphate buffer (pH 7.0). The limit of sensitivity using electrochemical detection was 100 pg on-column for all compounds with a signal-to-noise ratio of 3. Quantification of the compounds in human plasma and urine was possible down to 1 ng/ml (ca. 1 pmol). Pharmacokinetic results show that the sensitivity of the method is adequate for drug monitoring in clinical research.

Solid-phase extraction of vinblastine and vincristine from plasma and urine: variable drug recoveries due to non-reproducible column packings.

A sensitive and selective high-performance liquid chromatographic (HPLC) method for the determination of vinblastine and vincristine in plasma and urine is described. The drugs are isolated from 1.0 ml of the biological fluid with a solid-phase extraction column (Bond-Elut Diol). The HPLC method was combined with electrochemical detection at +850 mV versus an Ag/AgCl reference electrode. The detection limit is 100 pg for vinblastine and 250 pg for vincristine with a signal-to-noise ratio of 3, which permits the determination of these compounds in biological fluids at the nanogram level. Evaluation of the isolation method revealed that the drug recoveries and the reproducibility of the extraction procedure depend on the batch number of the solid-phase extraction column used.