Abstract
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.
Footnotes
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Send reprint requests to: Jean-Marie Nicolas, Department of Product Safety and Metabolism, UCB S.A. Pharma Sector, Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium.
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This work was performed in part at the University of Washington and supported by UCB S.A. Pharma Sector. A portion of this work was presented at the XIth International Symposium on Microsomes and Drug Oxidations, Los Angeles, 1996, and at the European Symposium on Prediction of Drug Metabolism in Man, Liège, 1998.
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↵2 Data on UCB files.
- Abbreviations used are::
- AcL
- carboxylic metabolite
- AED
- antiepileptic drug
- CYP
- cytochrome P-450
- ECOD
- 7-ethoxycoumarin O-deethylase
- EH
- epoxide hydrolase
- G6P
- glucose 6-phosphate
- G6PDH
- glucose 6-phosphate dehydrogenase
- UDPGA
- uridine 5′-diphosphoglucuronic acid
- UGT
- UDP-glucuronyltransferase
- Received May 14, 1998.
- Accepted October 27, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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