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Pharmacokinetics and metabolism of 14C-levetiracetam, a new antiepileptic agent, in healthy volunteers

  • Pharmacokinetics and Disposition
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Abstract

The absorption, disposition and metabolism of levetiracetam, a new antiepileptic drug, have been investigated after a single oral dose of the 14C-labelled molecule administered to male healthy volunteers. As chiral inversion can occur during drug metabolism, the chiral inversion of levetiracetam and/or of its major metabolite produced by hydrolysis (the corresponding acid) was also investigated. Finally, the in vitro hydrolysis of levetiracetam to its major metabolite and the inhibition of this reaction in human blood have been studied. Levetiracetam was very rapidly absorbed in man, with the peak plasma concentration of the unchanged drug occurring at 0.25–0.50 h. The unchanged drug accounted for a very high percentage of plasma radioactivity (97–82%) at all the times measured, i.e. until 48 h after administration. The apparent volume of distribution of the compound was close (0.55–0.62 l/kg) to the volume of total body water. Total body clearance (0.80–0.97 ml/min/kg) was much lower than the nominal hepatic blood flow. The plasma elimination half-life of the unchanged drug varied between 7.4 h and 7.9 h. Plasma to blood ratio of total radioactivity concentrations was 1.1–1.3, showing that radioactivity concentrations were similar in blood cells and plasma. The balance of excretion was very high in all four volunteers. The predominant route of excretion was via urine, accounting for a mean of 95% of the administered dose after 4 days. Two major radioactive components were present in urine, the unchanged drug and the acid obtained by hydrolysis, accounting for 66% and 24% of the dose after 48 h, respectively. Hydrolysis of levetiracetam in human blood followed Michaelis-Menten kinetics with Km and Vmax values of 435 µM and 129 pmol/min/ml blood, respectively. Among the inhibitory agents investigated in this study, only paraoxon inhibited levetiracetam hydrolysis (92% inhibition at 100 µM). Oxidative metabolism occurred in man, although it accounted for no more than 2.5% of the dose. There was no evidence of chiral inversion.

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Acknowledgement

The authors wish to thank B. Kenda and M. Plisnier for helpful discussion on the structures of reference standards and metabolites, C. Doumergue for documentation and M. Rovei for preparation of the manuscript. The experiments comply with the current laws of the country in which the experiments were performed.

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  1. UCB Pharma, 21 rue de Neuilly, 92003, Nanterre Cedex, France

    Margherita Strolin Benedetti

  2. UCB Pharma, Chemin du Foriest, 1420 Braine-l’Alleud, Belgium

    Rhys Whomsley & Eugène Baltes

  3. UCB Research Inc., 840 Memorial Drive, Cambridge , MA, 02139, USA

    Jean-Marie Nicolas

  4. Inveresk Research, EH33 2NE, Tranent , Scotland, UK

    Colin Young

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  1. Margherita Strolin Benedetti
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Correspondence to Margherita Strolin Benedetti.

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Strolin Benedetti, M., Whomsley, R., Nicolas, JM. et al. Pharmacokinetics and metabolism of 14C-levetiracetam, a new antiepileptic agent, in healthy volunteers. Eur J Clin Pharmacol 59, 621–630 (2003). https://doi.org/10.1007/s00228-003-0655-6

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