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Low Oral Bioavailability of Hexamethylmelamine in the Rat Due to Simultaneous Hepatic and Intestinal Metabolism

Faculty of Pharmacy, Department of Pharmacology and Pharmacotherapy [P. J. M. K., G. A. H., J. N.], and Department of Analytical Pharmacy [A. H., M-J. J. M.], State University of Utrecht, Catharijnesingel 60, 3511 GH Utrecht, The Netherlands

The disposition of both hexamethylmelamine (HMM) after intraarterial, i.v., portal vein, and intraduodenal administration and of pentamethylmelamine following its i.v. administration was studied in male Wistar rats. HMM (5 and 10 mg/kg) and pentamethylmelamine (5 mg/kg) were infused via implanted cannulas into conscious animals (n 4). Plasma levels of parent compound and of metabolites were determined by gas chromatography. The areas under the plasma concentration-time curves of HMM following its intraarterial and i.v. administration were not significantly different, indicating that HMM was not appreciably metabolized in the lung. Areas under plasma-concentration-time curves of HMM following portal vein and intraduodenal administration were 27 and 8% of the area under the plasma concentration-time curve after i.v. administration, respectively. Absorption of HMM was complete as judged from metabolite data. The reduced bioavailability of HMM intraduodenally was thus a consequence of presystemic elimination in the liver and the gut wall. Extraction ratios (or first-pass effects) of the liver and the gut wall were 73 and 71%, respectively. Linear kinetic behavior of HMM i.v. was observed in the 5- to 10-mg/kg dose range. Extensive gut wall metabolism may have important implications for the antitumor activity mechanism of HMM.

¹ To whom requests for reprints should be addressed.

Received 11/23/82. Accepted 4/ 5/83.

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