title: Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms.
abstract: OBJECTIVE
  Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug-drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding.
  
  
  METHODS
  A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell-based assays and primary human hepatocytes were used to elucidate induction of gene expression.
  
  
  RESULTS
  Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro, it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes.
  
  
  CONCLUSIONS
  Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X receptor (PXR). This negates a common effect of these drugs on CAR/PXR-dependent induction of drug metabolism and further provides an explanation for artemisinin consistently inducing cytochrome P450 genes in vivo, whereas arteether and artemether do not. All these drugs are metabolized very rapidly, but only artemisinin is converted to an enzyme-inducing metabolite. For better understanding of pharmacokinetic drug-drug interaction possibilities, the inducing properties of artemisinin metabolites should be considered.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Germany. oliver.burk@ikp-stuttgart.de
authors.forename: O
authors.initials: O
authors.lastname: Burk
authors.forename: R
authors.initials: R
authors.lastname: Piedade
authors.forename: L
authors.initials: L
authors.lastname: Ghebreghiorghis
authors.forename: J T
authors.initials: JT
authors.lastname: Fait
authors.forename: A K
authors.initials: AK
authors.lastname: Nussler
authors.forename: J P
authors.initials: JP
authors.lastname: Gil
authors.forename: B
authors.initials: B
authors.lastname: Windshügel
authors.forename: M
authors.initials: M
authors.lastname: Schwab
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology*; D037621:Artemisinins / Q000378:metabolism / Q000494:pharmacology*; D019556:COS Cells; D018938:Caco-2 Cells; D002522:Chlorocebus aethiops; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004347:Drug Interactions; D004351:Drug Resistance; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000090702:Constitutive Androstane Receptor; D008024:Ligands; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; C031327:artemisinin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human