Antimalarial Artemisinin Drugs Induce Cytochrome P450 and MDR1 Expression by Activation of Xenosensors Pregnane X Receptor and Constitutive Androstane Receptor

@article{Burk2005AntimalarialAD,
  title={Antimalarial Artemisinin Drugs Induce Cytochrome P450 and MDR1 Expression by Activation of Xenosensors Pregnane X Receptor and Constitutive Androstane Receptor},
  author={Oliver Burk and Katja A Arnold and Andreas K. Nussler and Elke Schaeffeler and Ekaterina Efimova and Bonnie A. Avery and Mitchell A. Avery and Martin F. Fromm and Michel F Eichelbaum},
  journal={Molecular Pharmacology},
  year={2005},
  volume={67},
  pages={1954 - 1965}
}
Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying… 

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References

SHOWING 1-10 OF 42 REFERENCES

The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution.

PXR is established as a promiscuous xenobiotic receptor that has diverged during evolution through the use of a novel scintillation proximity binding assay, which demonstrates that many of the compounds that induce CYP3A expression bind directly to human PXR.

Induction of drug metabolism: the role of nuclear receptors.

In this review, recent findings regarding xenosensors and their target genes are summarized and are put into an evolutionary perspective in regard to how a living organism has derived a system that is able to deal with potentially toxic compounds it has not encountered before.

Nuclear Receptor Response Elements Mediate Induction of Intestinal MDR1 by Rifampin*

Intestinal P-glycoprotein, which is encoded by the MDR1 gene, plays an important role in the absorption and presystemic elimination of many xenobiotics, and its induction is mediated by a DR4 motif in the upstream enhancer at about −8 kilobase pairs, to which PXR binds.

Pharmacokinetic Interactions of Antimalarial Agents

Although clinical studies have so far not shown any significant interactions, drug interactions should be given appropriate attention when other combinations are used, particularly in combination with other agents.

Identification of human cytochrome P450s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data

The results show that it is possible to make in vitro–in vivo predictions of high, intermediate and low CLint drug categories and the identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug–drug interactions in vivo.

Orphan Nuclear Receptors Constitutive Androstane Receptor and Pregnane X Receptor Share Xenobiotic and Steroid Ligands*

It is demonstrated that several of the compounds that regulate mouse and human CAR, including natural steroids, bind directly to the receptors and suggest that CAR, like PXR, is a steroid receptor that is capable of recognizing structurally diverse compounds.

Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4.

Three natural PXR protein variants may play a role in the observed interindividual variability of CYP3A4 expression and may be involved in rare, atypical responses to drugs or altered sensitivities to carcinogens.

The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux

It is shown that SXR also regulates drug efflux by activating expression of the gene MDR1, which encodes the protein P-glycoprotein (ABCB1) inCytochrome P450 3A4, an important mediator of drug catabolism that can be regulated by the steroid and xenobiotic receptor.

A Novel Distal Enhancer Module Regulated by Pregnane X Receptor/Constitutive Androstane Receptor Is Essential for the Maximal Induction of CYP2B6 Gene Expression*

Results show that a novel xenobiotic-responsive enhancer module in the distal region of the CYP2B6 promoter (CYP2B 6-XREM) together with the PBREM mediates optimal drug-induced expression ofCYP 2B6.

Transport of artemisinin and sodium artesunate in Caco-2 intestinal epithelial cells.

The results indicate that the transepithelial permeability is probably not a limiting factor in the overall absorption process after oral administration of artemisinin or sodium artesunate and solubility, dissolution rate, stability, and first-pass metabolism are suggested as alternative limiting factors.