Stereoselective Pharmacokinetic Analysis of Levetiracetam and Its Enantiomer in Dogs
Abstract number :
1.002
Submission category :
Year :
2000
Submission ID :
2331
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Nina Isoherranen, Boris Yagen, Michael Roder, Stefan Soback, Volker Schurig, Meir Bialer, Hebrew University, Jerusalem, Israel; Institute of Organic Chemistry University of Tubingen, Tubingen, Germany; Kimron Veterinary Institute, Beit Dagan, Israel; Hebr
RATIONALE: Levetiracetam ((S)-a-ethyl-2-oxo-pyrrolidine acetamide, LEV) is a new antiepileptic drug recently approved for use in refractory partial or generalized seizures. The chiral center in levetiracetam is in a-position to the butyramide group and therefore chiral inversion in vivo would appear possible. The purpose of this study was to evaluate and compare the pharmacokinetics of levetiracetam and (R)-a-ethyl-2-oxo-pyrrolidine acetamide (REV) in dogs.The in vivo racemization in dogs was also explored. METHODS: LEV and REV were synthesized by an enantioselective method and administered intravenously in a randomized crossover fashion to six dogs. The plasma and urine were collected and the concentrations of LEV and REV were established using a novel enantioselective gas chromatography-mass spectrometry assay. The pharmacokinetic analysis was performed using the noncompartmental approach. RESULTS: There was no statistically significant difference in the clearance (0.090 0.020 Lh-1kg-1 for both enantiomers) or volume of distribution at steady state (0.45 0.13 Lkg-1 and 0.51 0.11 Lkg-1 for LEV and REV respectively). However the half life (3.6 0.8 h and 4.3 0.8 h for LEV and REV respectively)and mean residence time (5.0 1.2 h and 6.0 1.1 h for LEV and REV respectively) of the enantiomers were statistically significantly different. A significant statistical difference was also observed in the renal clearance (0.77 0.21 Lh-1 and 1.10 0.3 Lh-1 for LEV and REV respectively) and the fraction excreted unchanged (50 5% and 71 10% of LEV and REV). The renal clearance of both enantiomers is much smaller than the GFR of a dog, suggesting tubular reabsorption. This reabsorption might be a cause of the observed enantioselectivity in the renal clearance. Since the total body clearance of the enantiomers was not different there might be enantioselective metabolism in which the metabolic clearance of LEV should be significantly higher than that of REV. CONCLUSIONS: This study showed that the pharmacokinetics of the two enantiomers in dogs is significantly different, however there is no chiral inversion of LEV to REV or vica versa.