Pharmacokinetics of methotrexate in the cerebrospinal fluid after intracerebroventricular administration in patients with meningeal carcinomatosis and altered cerebrospinal fluid flow dynamics
Pharmacokinetic parameters of the distribution and elimination of intracerebroventricularly administered methotrexate (MTX) were evaluated in three patients with meningeal carcinomatosis. Abnormal cerebrospinal fluid (CSF) flow dynamics, which were not otherwise clinically evident, were diagnosed by 111In-diethylenetriaminepentaacetate radionuclide imaging. Alterations in CSF flow resulted in large changes in MTX distribution. Reduced cortical convexity (type III), spinal subarachnoid (type II), or ventricular (type I) CSF flow resulted in a prolongation of the single-pass mean residence time of MTX in the peripheral compartment by as much as eightfold and a reduction in intercompartmental clearance by 94-99%. Leptomeningeal carcinomatosis can affect both CSF MTX distribution and elimination, each to a different extent, within the same patient. Total MTX clearance from the CSF was reduced by 79-93% in the patients studied. A two-compartment pharmacokinetic model, with elimination occurring from the peripheral compartment, gave values for the distribution rate constant from the central to the peripheral compartment (k12), which decreased with the extent of CSF flow abnormality. However, the elimination rate constant from the peripheral compartment (k20) was reduced to an extent apparently independent of CSF flow abnormality (percentage reduction in k12 and k20, respectively: type III, 18 and 66; type II, 67 and 86; type I, 78 and 48). Inadequate distribution and locally high concentrations of MTX within the CSF may contribute to therapeutic failure and neurotoxicity. Monitoring of MTX levels in the CSF may be deceiving when samples are drawn from the site of injection, since the distribution kinetics are altered by abnormal CSF flow dynamics.
- Research Organization:
- George Washington Univ. School of Medicine and Health Sciences, Washington, DC (USA)
- OSTI ID:
- 5877752
- Journal Information:
- Ther. Drug Monit.; (United States), Vol. 11:3
- Country of Publication:
- United States
- Language:
- English
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CARCINOMAS
DIAGNOSIS
CEREBROSPINAL FLUID
FLUID FLOW
MENINGES
METHOTREXATE
BIOCHEMICAL REACTION KINETICS
INDIUM 111
PATIENTS
RADIOISOTOPE SCANNING
ANTIMETABOLITES
BETA DECAY RADIOISOTOPES
BIOLOGICAL MATERIALS
BODY FLUIDS
COUNTING TECHNIQUES
DAYS LIVING RADIOISOTOPES
DISEASES
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
INDIUM ISOTOPES
INTERMEDIATE MASS NUCLEI
ISOMERIC TRANSITION ISOTOPES
ISOTOPES
KINETICS
MATERIALS
MEMBRANES
MINUTES LIVING RADIOISOTOPES
NEOPLASMS
NUCLEI
ODD-EVEN NUCLEI
RADIOISOTOPES
REACTION KINETICS
550601* - Medicine- Unsealed Radionuclides in Diagnostics