Toxicokinetics and metabolism of N-[14C]methylpyrrolidone in male Sprague-Dawley rats. A saturable NMP elimination process.
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 micro l/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 (t1/2 = 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.
Payan
Jean-Paul
JP
Institut National de Recherche et de Sécurité, Vandoeuvre Cedex, France. payanjp@inrs.fr
Beydon
Dominique
D
Fabry
Jean-Paul
JP
Boudry
Isabelle
I
Cossec
Benoit
B
Ferrari
Elisabeth
E
D000818:Animals; D002250:Carbon Radioisotopes / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D011760:Pyrrolidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
D002250:Carbon Radioisotopes; D011760:Pyrrolidinones; C038678:N-methylpyrrolidone