Notable Drug-Drug Interaction Between Etizolam and Itraconazole in Poor Metabolizers of Cytochrome P450 2C19.

Article Details

Citation

Yamamoto T, Furihata K, Hisaka A, Moritoyo T, Ogoe K, Kusayama S, Motohashi K, Mori A, Iwatsubo T, Suzuki H

Notable Drug-Drug Interaction Between Etizolam and Itraconazole in Poor Metabolizers of Cytochrome P450 2C19.

J Clin Pharmacol. 2017 Nov;57(11):1491-1499. doi: 10.1002/jcph.956. Epub 2017 Jul 5.

PubMed ID
28679023 [ View in PubMed
]
Abstract

In this study, impact of a polymorphism of CYP2C19 on drug-drug interaction (DDI) was examined for etizolam. The effect of itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics of etizolam (a substrate of CYP2C19 and CYP3A) was assessed in both extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19. Sixteen participants (8 EMs and 8 PMs) received a single oral dose of etizolam (0.25 mg) on day 1. The participants ingested itraconazole (200 mg twice a day) on days 2-5. On day 5, participants received an oral dose of etizolam (0.25 mg) again. Before coadministration of itraconazole (day 1), the area under the time-plasma concentration curve from time zero to infinity (AUCinfinity ) of etizolam was higher in PMs than in EMs (2.65-fold, P < .01). Coadministration of itraconazole increased the AUCinfinity of etizolam 1.66-fold and 2.34-fold in EMs and PMs, respectively (day 5). Consequently, AUCinfinity was 6.18-fold higher in PMs with itraconazole than that in EMs without itraconazole. The increase by itraconazole was larger in PMs (P < .01). In heterozygous EMs (hEMs), AUCinfinity was simulated to be 2.56-fold higher with itraconazole than that in EMs without itraconazole. We found that in vitro measurements of fraction metabolized (fm ) using the liver microsome prepared from PM donors would be helpful to predict polymorphism-dependent DDIs. These results suggest that the PMs and hEMs of a polymorphic CYP would be at higher risk of DDIs relative to EMs for drugs metabolized by both polymorphic and nonpolymorphic CYPs such as etizolam.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
EtizolamCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Details