Toxicokinetics and Metabolism ofN-[14C]Methylpyrrolidone in Male Sprague-Dawley Rats. A Saturable NMP Elimination Process

• Published in: Drug metabolism and disposition Vol. 30; no. 12; p. 1418
• Main Authors: Jean-Paul Payan, Dominique Beydon, Jean-Paul Fabry, Isabelle Boudry, Benoit Cossec, Elisabeth Ferrari
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.12.2002
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.30.12.1418

This study evaluated the toxicokinetics of N- [ 14 C]methylpyrrolidone ([ 14 C]NMP) after intravenous administration (0.1, 1, 10, 100, and 500 mg/kg, in saline solution) or topical application (20 and 40 μl/cm 2 ; 10 cm 2 , neat) in haired male Sprague-Dawley rats. Whatever the dose, unchanged NMP was intensively distributed into the body with a volume of distribution of 69% of body weight. After this phase, unchanged NMP declined almost linearly with time for 3 to 4 h after administration and then followed a mono-exponential function ( t ½ = 0.8 h) for the three lowest doses. The maximal plasma level of 5-hydroxy- N -methylpyrrolidone (5-HNMP), the main metabolite, was reached 4 to 6 h later for the three lowest doses and 8 to 24 h later for the highest doses. These findings indicate that the elimination of NMP is governed by a saturable metabolism process. The Michaelis-Menten parameters estimated from plasma levels of unchanged NMP were 2 mM and 3.8 mg/h, respectively. Between 4 and 10% of the administered doses were excreted in the urine as unchanged NMP. Urinary clearance of NMP (0.03 to 0.07 ml/min) indicates intensive tubular reabsorption. 5-HNMP was the main urinary metabolite and accounted for 42 to 55% of the administered doses. Its maximal urinary excretion occurred between 4 and 6 h after administration of the three lowest doses and between 8 and 24 h for the two highest doses. Urinary clearance (0.9 to 1.3 ml/min) was compatible with renal elimination by simple glomerular filtration.