Idea Transcript
[CANCER RESEARCH 41, 1466-1468, 0008-5472/81 /0041-OOOOS02.00
Pharmacokinetics
April 1981]
of Vincristine in the Cerebrospinal Fluid of Humans1
D. V. Jackson, Jr.,2 V. S. Sethi, C. L. Spurr, and J. M. McWhorter Oncology Research Center, Departments of Medicine [D. V. J., V. S. S., C. L S.] and Neurosurgery University, Winston-Salem, North Carolina 27103
MATERIALS
ABSTRACT Using a sensitive radioimmunoassay, concentrations of vincristine and its products were determined in cerebrospinal fluid (CSF) and corresponding blood samples from four patients with lymphoma and two patients with leukemia who had re ceived i.v. bolus injection of 2 mg vincristine. Serial samples of CSF were withdrawn from a CSF reservoir in two patients during a 24-hr period following injection. The first time point after injection at which measurable levels of vincristine were detected in the CSF was 30 min; the concentrations were within the lower range of sensitivity of the assay and were 20to 30-fold lower than were corresponding serum samples. Despite a prolonged terminal half-life of vincristine in the serum (14.4 to 37.5 hr) following i.v. bolus injection, concentrations of vincristine in the CSF ranged between undetectable within the limits of the assay and 1.1 x 10~9 M during the 24-hr period of observation. The highest CSF concentration of vin cristine (2.6 x 10"9 M) has been observed in a patient receiving cranial irradiation for active meningeal lymphoma. No measur able levels of vincristine or its products were detected in spot samples of CSF from three patients. Penetration of vincristine and its products into the CSF of humans after i.v. bolus injection appears to be very poor and may account for the uncommon occurrence of central neurotoxicity following its clinical use.
INTRODUCTION Vincristine, an alkaloid with antimitotic properties obtained from the plant Vinca rosea (L), has been widely used in cancer chemotherapy due to its lack of myelosuppression at conven tional dosage. Its principal limiting side effect has been neu rotoxicity which is usually manifested by a peripheral mixed sensory-motor neuropathy with symmetrical neurological signs and symptoms (8). Central neurological findings occur uncom monly and include confusion, depression, agitation, insomnia, hallucinations, psychosis, and hyponatremia as a result of inappropriate antidiuretic hormone secretion (8). Disruption of microtubules in neural tissue has been sug gested as the mechanism leading to neurotoxicity (4). However, little is known about the penetration of vincristine into the nervous system. Studies in the subhuman primate Macaca mulatta have shown rapid entry of this agent into the CSF3 with attainment of concentrations in the nM range (11 ). The current study was undertaken to investigate the pharmacokinetics of vincristine in the CSF of humans.
' Supported
in part by Grant CA 12197 from the National Cancer Institute,
NIH. 2 To whom requests for reprints should be addressed. 3 The abbreviations used are: CSF. cerebrospinal fluid; Received October 20, 1980; accepted January 13, 1981.
1466
i.t., intrathecal.
[J. M. M.]. Bowman Gray School of Medicine of Wake Forest
AND METHODS
Subjects. Four patients with non-Hodgkin's lymphomas (histiocytic, 1; mixed histiocytic-lymphocytic, 1; poorly differen tiated lymphocytic, 2) and 2 patients with acute lymphoblastic leukemia treated at the Bowman Gray School of Medicine were subjects of this study. Patient characteristics are given in Table 1. Meningeal involvement had been documented in each of the patients with lymphoma and was active in 2 of them at the time of study. One of the latter patients (W. G.) was receiving both cranial irradiation (900 rads) and i.t. methotrexate (15 mg given 5 days before study). Cranial irradiation consisting of 2300 rads had been administered to a second patient with lymphoma 7 months prior to study. Computerized tomography of the brain was performed in each of the patients with lymphoma and failed to demonstrate any evidence of mass lesions. Two pa tients with leukemia were investigated while receiving i.t. meth otrexate for central nervous system prophylaxis, of which the most recent injection was 7 days prior to study (K. M.). Sample Collection and Processing. Following i.v. injection of vincristine, serial samples of CSF were obtained from an indwelling ventricular catheter during a 24-hr period in 2 sub jects, and spot samples were collected by lumbar puncture in the 4 remaining patients. The total dose of vincristine used was 2 mg in each patient. Blood samples were obtained at intervals corresponding to CSF collection. Using a 23-gauge needle, periodic 1.0-ml samples of CSF were withdrawn from Rickham reservoirs (Extracorporeal Med ical Specialties, Inc., King of Prussia, Pa.) from 5 min to 24 hr following i.v. injection of vincristine in 2 patients with lymphoma (A. W. and E. M.). The first 1.0 ml of CSF was discarded prior to obtaining the test sample to ensure collection of a repre sentative ventricular specimen of CSF. Simultaneous venous blood samples were obtained by removal of 3 ml whole blood from the arm opposite injection or in the same arm below the site of vincristine administration. A 23-gauge scalp vein needle was attached to a heparin lock (Abbott Diagnostics, North Chicago, III.) from which blood samples were withdrawn after discarding the first 1.0 ml containing blood mixed with a dilute heparin solution. Blood samples were centrifuged, and the resultant sera were stored with the CSF samples at -20° until processed. In addition to determination of the concentration of vincris tine, CSF samples were analyzed for protein and glucose concentrations, cell count, cytology, and culture. In no patient was an accompanying bacterial meningitis present at the time of study. Radioimmunoassay and Pharmacokinetic Analysis. CSF and serum samples were analyzed for vincristine by radioim munoassay. The assay was originally developed by Root ef al. (13) and has been modified to allow a 5- to 7-fold greater sensitivity to 5 x 10~10 to 1 x 10"9 M (15). Appropriate dilution of the serum or CSF samples was made and assayed along CANCER
RESEARCH
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VOL. 41
Vincristine CSF Pharmacokinetics
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Table 1 Patient characteristics
involvementActiveActivePriorPriorNoneNoneCranial irradiationCurrent PatientW. (yr)546061661516SexMMMMMFDiagnosisLymphomaLymphomaLymphomaLymphomaLeukemiaLeukemiaMeningea! rads)NonePrior (900
G.W. M.W. M.A. W.S.S.K.
rads)NoneNoneNone (2300
I0'r-
M.Age
with standard vincristine sulfate samples (0.01 to 1.0 mg). From the known amount of vincristine sulfate and the percent age of bound radioactivity, a standard curve was plotted on a log-logit graph from which the amount of vincristine sulfate present in each diluted sample was determined. With the need to use undiluted samples in measuring concentrations 5.0 x 10~9 M were obtained in each of the corresponding serum samples (Table 3). However, measurable concentrations of vincristine were not detectable in any of the CSF collections with the exception of the 3-hr sample in Patient W. G. who had active meningeal lymphoma at the time of study. In addition, the latter patient had received 900 rads cranial irradiation at the time of study. There was no correlation between vincristine levels in the CSF and concentrations of glucose and protein or cell count in
30 60
8 12 16 TIME (hours)
( min x I hr )
20
24
Chart 1. Blood decay kinetics of vincristine equivalents following i.v. bolus injection of 2 mg vincristine in Patients E. M. O and A. W. (O) with their corresponding concentrations of vincristine equivalents in the CSF: •E. M.; •, A. W. A, time points at which samples of CSF were collected but did not contain any detectable vincristine equivalents within the extreme lower limits of the assay (~5 x 10~'° M). Accurate measurements of concentrations