TY - JOUR T1 - IN VITRO AND IN VIVO INHIBITORY EFFECT OF STIRIPENTOL ON CLOBAZAM METABOLISM JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 608 LP - 611 DO - 10.1124/dmd.105.007237 VL - 34 IS - 4 AU - Carole Giraud AU - Jean-Marc Treluyer AU - Elisabeth Rey AU - Catherine Chiron AU - Jean Vincent AU - Gérard Pons AU - Agnès Tran Y1 - 2006/04/01 UR - http://dmd.aspetjournals.org/content/34/4/608.abstract N2 - A metabolic interaction between stiripentol (STP), an anticonvulsant agent that inhibits the activity of several cytochromes P450 (P450s), and clobazam (CLB), a 1,5-benzodiazepine, used in association with STP in severe myoclonic epilepsy in infancy was observed in vivo. This interaction was characterized in vitro using cDNA-expressed CYP3A4 and CYP2C19 (main P450 involved in CLB metabolism) to calculate Ki and IC50 of stiripentol in comparison with ketoconazole (CYP3A4 inhibitor) and omeprazole (CYP2C19 inhibitor). STP inhibited N-demethylation of CLB to N-desmethylclobazam (NCLB) mediated by CYP3A4 (noncompetitively) and CYP2C19 (competitively) with Ki = 1.59 ± 0.07 and 0.516 ± 0.065 μM and IC50 = 1.58 μM [95% confidence interval (CI95%) = 1.20–2.08] and 3.29 μM (CI95% = 1.87–5.79), respectively. STP inhibited also more strongly the 4′-hydroxylation of NCLB to 4′-hydroxy-N-desmethylclobazam by CYP2C19 [competitive interaction with Ki = 0.139 ± 0.025 μM and IC50 = 0.276 μM (CI95% = 0.206–0.371)]. The inhibitory effect of STP on CLB demethylation by CYP3A4 was much weaker than that of ketoconazole [IC50 = 0.023 μM (CI95% = 0.016–0.033)], whereas its effect on NCLB hydroxylation by CYP2C19 was much higher than that of omeprazole [IC50 = 2.99 μM (CI95% = 2.11–4.24)]. The major in vitro inhibitory effect of STP on CLB metabolism and mostly on NCLB biotransformation is consistent with the changes in vivo in CLB and NCLB plasma concentrations in children treated by the association CLB/STP. The American Society for Pharmacology and Experimental Therapeutics ER -