This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Benvenuto, J. A. Articles by Loo, T. L. Search for Related Content PubMed PubMed Citation Articles by Benvenuto, J. A. Articles by Loo, T. L.

Pharmacology of Pentamethylmelamine in Humans¹

Section of Pharmacology, Department of Developmental Therapeutics, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030

A rapid, specific high-pressure liquid chromatographic assay was used to study the pharmacology of pentamethylmelamine in 21 patients (28 infusions) receiving 80 to 1500 mg/sq m. In patients with normal liver function, pentamethylmelamine was rapidly cleared from the plasma with a terminal half-life of 2.2 hr. Abnormal liver function tended to correlate with increased half-life and reduced total clearance. In addition, increased neurological toxicity was associated with hepatic abnormalities. The N²,N²,N⁴,N⁶-tetramethylmelamine, N²,N⁴,N⁶-trimethylmelamine, dimethylmelamine, and monomethylmelamine metabolites were detected in plasma. The terminal plasma half-lives of these metabolites increased with decreasing number of methyl group. With liver dysfunction, the plasma clearance of these metabolites also decreased and central nervous system toxicity increased. Although the antitumor activity of pentamethylmelamine is thought to be mediated by the intermediate hydroxymethyl metabolites produced by hepatic microsomal oxidation or by the formaldehyde generated, the neurological toxicity appears to depend upon the pharmacokinetics of the drug and its demethylated metabolites.

¹ Supported by Contracts NO1-CM 87185 and NO1-CM 43801 and Grants CA 14528 from the Division of Cancer Treatment, National Cancer Institute, NIH, USPHS, and contract CA 11430 from the Division of Cancer Cause and Prevention.

² To whom requests for reprints should be addressed.

³ Present address: Ontario Cancer Foundation, Ottawa General Hospital, Ottawa, Ontario, Canada.

⁴ Junior Faculty Fellow, American Cancer Society.

Received 9/ 2/80. Accepted 11/ 3/80.