Abstract
This study evaluated the toxicokinetics ofN-[14C]methylpyrrolidone ([14C]NMP) after intravenous administration (0.1, 1, 10, 100, and 500 mg/kg, in saline solution) or topical application (20 and 40 μl/cm2; 10 cm2, 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 (t½ = 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.
Footnotes
- Abbreviations used are::
- NMP
- N-methyl-2-pyrrolidone
- 5-HNMP
- 5-hydroxy-N-methylpyrolidone
- 2-HNMS
- 2-hydroxy-methylsuccinimide
- NMS
- N-methylsuccinimide
- [14C]NMP
- radiolabeledN-[14C]methylpyrrolidone
- HPLC
- high performance liquid chromatography
- AUC
- area under the curve
- Cl
- clearance
- Received April 8, 2002.
- Accepted August 13, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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