Abstract

Artemisinin drugs have become the first-line antimalarials in areas of multi-drug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of CYP-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism. To better understand the autoinduction and metabolic drug-drug interactions (DDIs), we evaluated the cytochrome P450s (especially CYP2B6 and 3A4) inhibited or induced by two artemisinin drugs, artemisinin (QHS) and dihydroartemisinin (DHA) using HLM, recombinant CYP enzymes and primary human hepatocytes. The results suggested that QHS was a weak reversible inhibitor of CYP2B6 (K_i, 4.6 μM) but not CYP3A4 (IC₅₀, ~50 μM) and did not show measurable time dependent inhibition of either CYP2B6 or 3A4. DHA inhibited neither CYP2B6 nor 3A4 (IC₅₀ > 125 μM). Additionally, it was found that QHS induced the activity of CYP3A4 (E_max 3.5-fold and EC₅₀ 5.9 μM) and CYP2B6 (E_max 1.9-fold and EC₅₀ 0.6 μM). Of the other CYPs, UGTs and transporters studied, QHS and DHA had no significant effect except for minor induction of mRNA expression of CYP1A2 (E_max 7.9-fold and EC₅₀ 5.2 μM) and CYP2A6 (E_max 11.7-fold and EC₅₀ 4.0 μM) by QHS. Quantitative prediction of CYP-mediated DDIs indicate autoinduction of QHS clearance with the AUCi/AUC ratio decreasing to 59%, as a result of a 1.9-fold increase in CYP3A4 and a 1.6-fold increase in CYP2B6 activity. These data suggest that QHS drugs are potential inducers of P450 enzymes, and the possible drug interactions (or lack thereof) with artemisinin drugs may be clinically relevant.