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

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 (AUC ) of etizolam was higher in PMs than in EMs (2.65-fold, P < .01). Coadministration of itraconazole increased the AUC of etizolam 1.66-fold and 2.34-fold in EMs and PMs, respectively (day 5). Consequently, AUC 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), AUC 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 (f ) 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.

Etizolam: A rapid review on pharmacology, non‐medical use and harms

“…Carbamazepine (a CYP3A4 inducer) increases etizolam metabolism , and itraconazole (a CYP3A4 inhibitor) inhibits it , indicating that interactions may occur with these drugs. CYP2C19 polymorphism can place poor metabolisers at higher risk of a drug–drug interaction . CYP2C19 deficiency may lead to side effects or toxicity with etizolam .…”

Effect of Drug Combination on Omeprazole Metabolism by Cytochrome P450 2C19 in <i>Helicobacter pylori</i> Eradication Therapy

“…21) On the other hand, itraconazole, ketoconazole, erythromycin, and clarithromycin each inhibit the metabolism of imidafenacin by decreasing the metabolic activity of CYP3A4. 22) Although CYP3A4 could reasonably enable DDIs owing to its wide substrate cavity, a recent study showed that etizolam metabolism by another isoform, CYP2C19, is affected by co-administration of itraconazole. 23) CYP2C19 is one of the major CYP isoforms 17) and is responsible for metabolism of at least 10% of commonly used clinical drugs.…”

Pharmacokinetic interaction between peimine and paeoniflorin in rats and its potential mechanism

“…Peimine was previously reported to exert inhibitory effects on the activity of various cytochrome P450 enzymes (CYP450s), including CYP3A4, 2E1 and 2D6, which are key mediators during the pharmacokinetics of various xenobiotics, including paeoniflorin (Li et al 2020). Previously, the inhibition or induction of CYP450s was considered as the main cause of the adverse drug-drug interaction between different drugs, which has been widely reported (Geffrey et al 2015;Yamamoto et al 2017;Nishihara et al 2019). It is speculated that the co-administration of peimine and paeoniflorin would induce drug-drug interaction, which might lead to failure of treatment or even drug toxicity.…”