RT Journal Article
SR Electronic
T1 Effect of Gemfibrozil on the Metabolism of Brivaracetam In Vitro and in Human Subjects
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1466
OP 1472
DO 10.1124/dmd.112.045328
VO 40
IS 8
A1 Nicolas, J.-M.
A1 Chanteux, H.
A1 Rosa, M.
A1 Watanabe, S.
A1 Stockis, A.
YR 2012
UL http://dmd.aspetjournals.org/content/40/8/1466.abstract
AB Brivaracetam (BRV) is a new high-affinity synaptic vesicle protein 2A ligand in phase III for epilepsy. Initial studies suggested that the hydroxylation of BRV into BRV-OH is supported by CYP2C8. Other metabolic routes include hydrolysis into a carboxylic acid derivative (BRV-AC), which could be further oxidized into a hydroxy acid derivative (BRV-OHAC). The aim of the present study was to investigate the effect of gemfibrozil (CYP2C9 inhibitor) and its 1-O-β-glucuronide (CYP2C8 inhibitor) on BRV disposition both in vivo (healthy participants) and in vitro (human liver microsomes and hepatocytes). In a two-period randomized crossover study, 26 healthy male participants received a single oral dose of 150 mg of BRV alone or at steady state of gemfibrozil (600 mg b.i.d). Gemfibrozil did not modify plasma and urinary excreted BRV, BRV-OH, or BRV-AC. The only observed change was a modest decrease (approximately −40%) in plasma and urinary BRV-OHAC. In human hepatocytes and/or liver microsomes, gemfibrozil potently inhibited the hydroxylation of BRV-AC into BRV-OHAC (Ki 12 μM) while having a marginal effect on BRV-OH formation (Ki ≥153 μM). Gemfibrozil-1-O-β-glucuronide had no relevant effect on either reaction (Ki >200 μM). In conclusion, gemfibrozil did not influence the pharmacokinetics of BRV and its hydroxylation into BRV-OH. Overall, in vitro and in vivo data suggest that CYP2C8 and CYP2C9 are not involved in BRV hydroxylation, whereas hydroxylation of BRV-AC to BRV-OHAC is likely to be mediated by CYP2C9.