Effects of artemisinin antimalarials on Cytochrome P450 enzymesin vitrousing recombinant enzymes and human liver microsomes: potential implications for combination therapies

Abstract

1. Cytochrome P450 enzyme system is the most important contributor to oxidative metabolism of drugs. Modification, and more specifically inhibition, of this system is an important determinant of several drug-drug interactions (DDIs). 2. Effects of the antimalarial agent artemisinin and its structural analogues, artemether, artesunate and dihydroartemisinin, on seven of the major human liver CYP isoforms (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4) were evaluated using recombinant enzymes (fluorometric assay) and human liver microsomes (LC-MS/MS analysis). Inhibitory potency (IC50) and mechanisms of inhibition were evaluated using nonlinear regression analysis. In vitro-in vivo extrapolation using the [I]/Ki ratio was applied to predict the risk of DDI in vivo. 3. All compounds tested inhibited the enzymatic activity of CYPs, mostly through a mixed type of inhibition, with CYP1A2, 2B6, 2C19 and 3A4 being affected. A high risk of interaction in vivo was predicted if artemisinin is coadministrated with CYP1A2 or 2C19 substrates. 4. With respect to CYP1A2 inhibition in vivo by artemisinin compounds, our findings are in line with previously published data. However, reported risks of interaction may be overpredicted and should be interpreted with caution.

Artemether Exhibits Amoebicidal Activity against Acanthamoeba castellanii through Inhibition of the Serine Biosynthesis Pathway

“…Among these derivatives, dihydroartemisinin showed the strongest amoebicidal activity, followed by artemether, whereas artemisinin and artesunate exhibited no significant effects during the treatment. The differences in the amoebicidal activity among the artemisinin derivatives may be associated with their different metabolism in the cells (29). The concentration of artemether used on Acanthamoeba trophozoites is higher than that for malaria (10) but similar to that used on blood lymphocytes and gastric cancer cells where necrosis occurs at artemether concentrations of 238.8 and 477.6 g/ml (15).…”

In vitro inhibitory effects of dihydromyricetin on human liver cytochrome P450 enzymes

“…However, an observed in vitro inhibition of a CYP enzyme does not mean that the drug will cause clinically relevant interactions. Many other factors might influence drug interactions mediated by CYP inhibition, including the contribution of the hepatic clearance to the total clearance of the affected drug, the fraction of the hepatic clearance which is subject to metabolic inhibition, and the ratio of the inhibition constant (Ki) over the in vivo concentration of the inhibitor (Ito et al 1998;Ericsson et al 2014). Therefore, further in vivo studies are needed to identify the interactions of DHM with CYP isoform in humans.…”

In vitro inhibitory effects of cepharanthine on human liver cytochrome P450 enzymes

“…However, the in vitro inhibition of CYP enzymes cannot ascertain the drug will cause clinically relevant interactions. Drug interaction mediated by CYP inhibition can be influenced by various factors, such as the contribution of the hepatic clearance during the metabolism of the drug, the fraction of the hepatic clearance which is subject to the inhibition of metabolism, and the ratio of the inhibition constant (Ki) over the in vivo concentration of the inhibitor (Ito et al 1998;Ericsson et al 2014). Therefore, further in vivo studies are essential for the interaction between CEP and CYP enzymes.…”