First-pass metabolism of pentamethylmelamine in the rat liver.

The disposition of pentamethylmelamine (PMM) was studied in the male Wistar rat. PMM (5 mg/kg) was administered intraarterially, i.v. (5 and 10 mg/kg), via the portal vein, and into the duodenum to cannulated and unanesthetized rats (n greater than or equal to 4) via infusion. Parent compound and metabolites were quantified by gas chromatography. The areas under the plasma concentration-time curves of PMM after intraarterial and i.v. administration were equal and twice as large as the areas after portal vein and intraduodenal administration. This indicated insignificant lung metabolism for PMM; the low bioavailability of PMM when given via the portal vein or intraduodenally (in both cases, some 50% of an i.v. dose) was the result of presystemic metabolism in the liver. PMM was completely absorbed after intraduodenal administration, and no intestinal metabolism was observed. Linear kinetic behavior of i.v. PMM was observed in the 5- to 10-mg/kg dose range. The area under the plasma concentration-time curve of the first metabolite N2,N2,N4,N6-tetramethylmelamine was significantly greater when PMM was given via the portal vein or intraduodenally than when given intraarterially or i.v. This indicated either extrahepatic elimination/renal excretion of PMM or the existence of an additional metabolic pathway. However, experiments with adrenalectomized rats and rats with ligated blood flow to the kidneys did not alter the area for the first metabolite. These findings may be explained by the formation of unknown metabolites and/or reactive intermediates of PMM.