TY - JOUR T1 - In Vitro Evaluation of Potential Drug Interactions With Levetiracetam, A New Antiepileptic Agent JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 250 LP - 254 VL - 27 IS - 2 AU - Jean-Marie Nicolas AU - Philippe Collart AU - Brigitte Gerin AU - Gary Mather AU - William Trager AU - Rene Levy AU - Jose Roba Y1 - 1999/02/01 UR - http://dmd.aspetjournals.org/content/27/2/250.abstract N2 - Levetiracetam and its carboxylic metabolite (AcL) were tested for their potential inhibitory effect on 11 different drug metabolizing enzyme activities using human liver microsomes. The following specific assays were investigated: testosterone 6β-hydroxylation [cytochrome P-450 3A4 (CYP3A4)], coumarin hydroxylation (CYP2A6), (R)-warfarin hydroxylation (CYP1A2), (S)-mephenytoin hydroxylation (CYP2C19),p-nitrophenol hydroxylation (CYP2E1) tolbutamide hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), epoxide hydrolase and UDP-glucuronyltransferase (UGT) toward paracetamol (UGT1*6), ethinyloestradiol (UGT1*1),p-nitrophenol (UGT(pl 6.2)), and valproic acid. None of these activities were affected by levetiracetam or AcL added at concentrations up to 1 mM. Additionally, primary cultures of rat hepatocytes were used to assess a potential inducing effect of levetiracetam on CYPs. Phenobarbital (2 mM), β-naphtoflavone (40 μM), dexamethasone (1 μM), and phenytoin (up to 300 μM) were tested as positive controls. When added to cells for 48 h, all the positive controls increased 7-ethoxycoumarinO-deethylase activity demonstrating the inducibility of CYPs in the present culture conditions. By contrast, levetiracetam did not affect the activity up to 1 mM. The highest levetiracetam concentrations examined in the above in vitro studies are well in excess of those measured in the plasma of patients receiving therapeutic doses. It is thus concluded that levetiracetam is unlikely to produce pharmacokinetic interactions through inhibition of CYPs, UGTs, and epoxide hydrolase. Furthermore, based on the in vitro assays with rat hepatocytes, it could be speculated that levetiracetam does not act as a CYP inducer. The American Society for Pharmacology and Experimental Therapeutics ER -