author={Yong Huang and Hideaki Okochi and Barnaby C. H. May and Giuseppe Legname and Stanley B. Prusiner and Leslie Z. Benet and B. Joseph Guglielmo and Emil T. Lin},
  journal={Drug Metabolism and Disposition},
  pages={1136 - 1144}
Quinacrine (QA), an antimalarial drug used for over seven decades, has been found to have potent antiprion activity in vitro. To determine whether QA can be used to treat prion diseases, we investigated its metabolism and ability to traverse the blood-brain barrier in mice. In vitro and in vivo, we identified by liquid chromatography-tandem mass spectrometry the major metabolic pathway of QA as N-desethylation and compared our results with an authentic reference compound. The major human… 

Figures and Tables from this paper

Pharmacokinetics of Quinacrine Efflux from Mouse Brain via the P-glycoprotein Efflux Transporter

It is argued that the inhibition of the P-gp efflux transporter should improve the poor pharmacokinetic properties of quinacrine in the CNS.

Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions

This work proposes that quinacrine eliminates a specific subset of PrPSc conformers, resulting in the survival of drug-resistant prion conformations, by utilizing MDR0/0 mice that are deficient in mdr1a andmdr1b genes.

Quinacrine, an Antimalarial Drug with Strong Activity Inhibiting SARS-CoV-2 Viral Replication In Vitro

The data show that Qx reduces SARS-CoV-2 virus replication and virus cytotoxicity, apparently by inhibition of viral ensemble, as observed by ultrastructural images, suggesting thatQx could be a potential drug for further clinical studies against coronavirus disease 2019 (COVID-19) infection.

Determination of quinacrine dihydrochloride dihydrate stability and characterization of its degradants.

Using computational approaches, the analysis of the potential toxicity of the impurities compared with the parent compound one shows that ketone and O-demethyl derivatives may exhibit specific toxicity profiles.

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

The collective findings give insight into the contribution of polymorphic P450 3A5 to drug metabolism and adverse drug interactions.

Repurposing of Anti-Malarial Drug Quinacrine for Cancer Treatment: A Review

Most of the research conducted over several decades to uncover new molecular mechanisms activated or inactivated and directly correlate with antineoplastic activity QC are summarized.

Pharmacokinetics and Metabolism of Acridine Drugs

Despite pharmacokinetic limitation for transport of intercalators, the design of acridines with efficient diffusion to tumor tissue is possible and can be improved by conjugation with various nanoobjects such as liposomes or dendrimers.

Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents

It is found that quinacrine stabilizes p53 and induces p53-dependent and independent cell death and synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafanib to delay tumor growth in vivo.

Autophagic flux inhibition and lysosomogenesis ensuing cellular capture and retention of the cationic drug quinacrine in murine models

In vitro and in vivo, V-ATPase-mediated cation sequestration is associated, above a certain threshold, to autophagic flux inhibition and feed-back lysosomogenesis, and ancillary experiments did not support that low micromolar concentrations of quinacrine are substrates for organic cation transporters-1 to -3 or P-glycoprotein.



Uptake and Efflux of Quinacrine, a Candidate for the Treatment of Prion Diseases, at the Blood-Brain Barrier

It is suggested that quinacrine transport at the blood–brain barrier is mediated by the efflux system (P-gp) and the influx system (organic cation transporter-like machinery).

Toxicity of Quinacrine Can Be Reduced By Co-Administration of P-Glycoprotein Inhibitor in Sporadic Creutzfeldt-Jakob Disease

Low-dose quinacrine with verapamil can be used as safe treatment of CJD and improvement of clinical findings was observed at the same level without any adverse effects.

Hepatic microsome studies are insufficient to characterize in vivo hepatic metabolic clearance and metabolic drug-drug interactions: studies of digoxin metabolism in primary rat hepatocytes versus microsomes.

  • Justine L. LamL. Benet
  • Biology, Medicine
    Drug metabolism and disposition: the biological fate of chemicals
  • 2004
The results strongly suggest that the hepatic uptake and efflux transporters that are found in hepatocytes, but not in microsomes, modulate intracellular concentration of digoxin and thus affect metabolism.

A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in a ovine model of scrapie

Investigation of possible pharmacokinetic and/or pharmacodynamic explanations for the discrepancy between the proven action of quinacrine in vitro and its lack of clinical efficacy concluded that the measurement in vitro of the antiprion EC50 in both intra‐ and extracellular biophases should be determined to avoid in vivo trials for which failure can be predicted.

Evaluation of Quinacrine Treatment for Prion Diseases

Despite its ability to cross the blood-brain barrier, the use of quinacrine for the treatment of CJD is questionable, at least as a monotherapy, and the multistep experimental approach employed here could be used to test new therapeutic regimes before their use in human trials.

Pharmacokinetics of quinacrine in the treatment of prion disease

If quinacrine penetrates brain tissue in concentrations exceeding that demonstrated for in vitro inhibition of PrPSc, it may be useful in the treatment of prion disease, and particularly extensive distribution was observed in spleen and liver tissue.

Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease

It is reported here that tricyclic derivatives of acridine and phenothiazine exhibit half-maximal inhibition of PrPSc formation at effective concentrations (EC50) between 0.3 μM and 3 μM in cultured cells chronically infected with prions.

Urinary metabolism of chloroquine.

The study gave no evidence for a dose-dependent formation of the three previously unknown metabolites ofchloroquine, and an artifact generated from chloroquine-N-oxide could be characterized by gas chromatography/mass spectrometry.

Effect of Aliphatic Side-Chain Substituents on the Antimalarial Activity and on the Metabolism of Primaquine Studied Using Mitochondria and Microsome Preparations

Primaquine, the α-dideutero analogue, and theα-methyl analogue were all found to have about the same in vitro antimalarial activity as determined in the liver hepatocyte assay.

Results of Quinacrine Administration to Patients with Creutzfeldt-Jakob Disease

Although its antiprion activity in the human brain has yet to be proved, these modest effects of quinacrine suggest the possibility of using chemical intervention against prion diseases.