In Vitro Evaluation of Potential Drug Interactions With Levetiracetam, A New Antiepileptic Agent

• Published in: Drug metabolism and disposition Vol. 27; no. 2; pp. 250 - 254
• Main Authors: NICOLAS, J.-M, COLLART, P, GERIN, B, MATHER, G, TRAGER, W, LEVY, R, ROBA, J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-02-1999
• Subjects: Animals; Anticonvulsants - metabolism; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Biomarkers; Butyrates - pharmacology; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Epoxide Hydrolases - antagonists & inhibitors; Glucuronosyltransferase - antagonists & inhibitors; Humans; In Vitro Techniques; Liver - cytology; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Neuropharmacology; Pharmacology. Drug treatments; Piracetam - analogs & derivatives; Piracetam - metabolism; Piracetam - pharmacology; Pyrrolidinones - pharmacology; Rats; Rats, Sprague-Dawley; Rat; Isozyme; Metabolite; Liver; Glycosyltransferases; Anticonvulsant; Epoxide hydrolase; Enzymatic activity; Inhibition; Human; UDP-glucuronosyltransferase; Digestive system; Enzyme; Induction; Transferases; Cytochrome P450; Rodentia; In vitro; Vertebrata; Mammalia; Animal; Ether hydrolases; Hydrolases; Hexosyltransferases; Levetiracetam
• ISSN: 0090-9556; 1521-009X

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-ethoxycoumarin O -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.