Human central nervous system pharmacology of pentamethylmelamine and its metabolites

Abstract

Pentamethylmelamine (PMM) 80 mg/ m2 was administered IN. to 8 patients during surgical resection of intracerebral tumors. PMM concentrations in tumors were generally much higher than concurrent plasma concentrations, ranging from undetectable (< .01 μg/g) to as high as 4.47 μg/g and were much higher in malignant melanoma samples than in astrocytoma samples. PMM was barely detectable or undetectable in most samples of edematous brain tissue adjacent to intracerebral tumor and in temporalis muscle. The PMM metabolites tetramethylmelamine (TeMM), trimethylmelamine (TrMM), and dimethylmelamine (University of Texas Cancer Center M.D. Anderson Hospital and Tumor Institute, Houston, Texas, USADMM) were each detectable in tumor samples from one or two patients. Monomethylmelamine (MMM) was present in tumor samples from all except one patient. MMM was noted in samples of edematous brain tissue adjacent to tumor from 4 of 8 patients. It was the only PMM metabolite found in brain. TrMM, DMM, and MMM but not PMM, and TeMM were found in tumor cyst fluid from a patient with an intracerebral malignant melanoma.

Two patients receiving therapeutic doses of PMM had biopsies taken of subcutaneous malignant melanoma deposits. PMM was undetectable in samples from one patient but reached high concentrations in the other patient. In both patients, MMM was the major metabolite. There was no indication that PMM penetrated into extracerebral tumors more readily than into intracerebral tumors.

Cerebrospinal fluid (CSF) samples were obtained from one patient without neurological toxicity who received low doses of PMM and from 4 patients receiving high doses of PMM who had developed neurological toxicity. In each case, PMM was barely detectable or undetectable in the cerebrospinal fluid while TeMM was found in only one sample. TrMM was detectable in CSF from all 5 patients and DMM was found in CSF from 4 of the 5 patients. MMM was detected in CSF from 3 of the 4 patients with neurological toxicity but was undetectable in CSF from the patient without neurological toxicity.

Thus, PMM penetrates readily into human intracerebral tumors but the concentrations attained may vary with the histology. PMM metabolites attained higher concentrations in brain and CSF than did PMM itself and may account for the drug's neurological toxicity.