Comparative pharmacology of pentamethylmelamine and hexamethylmelamine in mice.

Abstract

The comparative pharmacology of pentamethylmelamine (PMM) and hexamethylmelamine (HMM) was determined in mice. PMM administered i.p. at one-tenth of a lethal dose (175 mg/kg) produced a maximum 18% reduction in the peripheral white blood cell count of normal mice. This same dose of PMM produced 70% inhibition of DNA synthesis in Lieberman plasmacytoma ascites cells 48 hr after drug administration. HMM administered i.p. at one-tenth of a lethal dose (200 mg/kg) inhibited Lieberman plasmacytoma DNA synthesis by 80% at 48 hr. The time course of tumor cell RNA synthesis inhibition was comparable for the two drugs, with a maximum 60% inhibition at 8 hr postinjection and recovery to only 20 to 30% inhibition at 72 hr. The pharmacological disposition of PMM in mice was compared to HMM after i.p. administration of one-tenth of a lethal dose of ring -14C-labeled drug. Concentration of intact drug in plasma and tissues was determined by high-pressure liquid chromatography. Both HMM and PMM disappeared rapidly from the plasma with a half-life of approximately 40 min. In contrast to these results with intact drug, the peak plasma level of radiolabel was attained at 1 hr after administration for both compounds. The highest tissue concentrations of [ ring -14C]PMM or HMM were found in the liver and small intestine. Despite the increased water solubility of PMM, the peak concentration of radiolabel in the brain at 4 min after injection was 3-fold higher than that attained with HMM, and the maximum concentration of PMM in the brain after PMM was 14-fold higher than that attained after HMM. Neurotoxicity, including flaccid paralysis, was observed in the mice within 15 min after PMM administration and continued for 4 to 5 hr.