TABLE 4

Drug-drug interaction summary

CES1 InhibitorsCES1 SubstratesInteraction Summary
AlcoholMethylphenidateMany in vitro and in vivo studies confirmed alcohol inhibits CES1 and mediates biotransformation of methylphenidate to ethylphenidate; methylphenidate plasma concentrations were increased when patients took methylphenidate with alcohol (Griffin et al., 2010, 2013; Bell et al., 2011a,b; Zhu et al., 2011, 2017; Patrick et al., 2013; Parker et al., 2015).
AlcoholOseltamivirWhen alcohol was administered with oseltamivir in humans, the AUC of oseltamivir increased by 37% (Hu et al., 2014).
CannabisOseltamivirIn vitro study with CES1-transfected cells suggested THC, CBD, and CBN to be the potent CES1 inhibitors. The inhibition constant (Ki) values for THC, CBD, and CBN were 0.541, 0.974, and 0.263 µM (0.170, 0.306, and 0.0817 µg/ml) (Qian et al., 2019).
Protease InhibitorsMethylphenidate. PNPA and p-nitrophenol (PNP)In vitro study showed that protease inhibitors (i.e., nelfinavir, amprenavir, atazanavir, ritonavir, and saquinavir) inhibited the catalytic activity of CES1 (P < 0.01). Among protease inhibitors, nelfinavir had a significantly higher inhibitory effect compared with other agents (Rhoades et al., 2012).
AripiprazoleMethylphenidate, PNPAIn vitro study suggested aripiprazole, perphenazine, thioridazine, and fluoxetine to be potent inhibitors of CES1. Among the medications tested, aripiprazole was the most potent inhibitor of CES1, and an in vivo study with FVB mouse confirmed this result (Zhu et al., 2010).
Isradipine/TacrolimusPNPA, trandolaprilIn vitro study with human liver microsomes suggested isradipine [dihydropyridine calcium antagonist (DHP)] and tacrolimus (immunosuppressive agent) to be potent CES1 inhibitors (Thomsen et al., 2014).
ValproateRufinamideIn vitro study suggested valproate could inhibit CES1 function and affect rufinamide metabolism (Williams et al., 2011).
ACEIClopidogrelACEIs and clopidogrel are often administered together as both of them are cardiovascular medications; both ACEIs and clopidogrel are suggested to be inhibitors of CES1. A clinical study with patients with myocardial infarction (n = 70,934) demonstrated concomitant use of ACEIs increased the rate of clinically significant bleeding compared with the clopidogrel monotherapy (P = 0.002) (Kristensen et al., 2014). Another clinical study with patients with myocardial infarction (n = 45,918) with clopidogrel showed that concomitant use of clopidogrel and ACEI (perindopril and ramipril) was not associated with the re-infarction, heart failure or death (Cressman et al., 2015).