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Impact of cerebral malaria on brain distribution of mefloquine

Sylvie Barraud de Lagerie1, Christine Fernandez, Michèle German-Fattal

  • 1University of Paris-Sud 11, Clinical Pharmacy Unit EA 2706, 5 rue JB Clément, Chatenay-Malabry, 92296, France. sylvie.vilatte@psl.aphp.fr

Drug Metabolism Letters
|April 10, 2009
PubMed

Insights

Cerebral malaria (CM) in mice reduced mefloquine (MQ) brain uptake. This suggests that increased central toxicity from MQ is unlikely during CM, despite its transport across the blood-brain barrier.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Infectious Diseases

Background:

  • Cerebral malaria (CM) is a severe complication of Plasmodium falciparum malaria.
  • The blood-brain barrier (BBB) regulates drug entry into the brain, involving efflux pumps like P-glycoprotein (P-gp) and Breast Cancer Resistant Protein (BCRP).
  • Inflammation and infection can alter BBB function and drug transport.

Purpose of the Study:

  • To investigate the impact of CM on the cerebral uptake of mefloquine (MQ).
  • To explore the role of BBB transporters in altered MQ brain concentrations during CM.
  • To assess the potential for increased central toxicity of MQ in CM.

Main Methods:

  • An experimental model of CM using Plasmodium berghei ANKA (PbA) infected mice.
  • Measurement of MQ concentrations in blood and brain tissue using liquid chromatography after a single IP dose.
  • Comparison of MQ brain/plasma ratios between CM and non-infected control mice.

Main Results:

  • MQ brain concentrations were significantly decreased in CM mice compared to healthy mice (brain/plasma ratio of 0.77 vs. 1.31).
  • The observed reduction in MQ brain transport was not attributed to altered P-gp function.
  • CM itself reduces MQ transport into the brain.

Conclusions:

  • Cerebral malaria reduces the brain uptake of mefloquine in a mouse model.
  • Increased central toxicity due to mefloquine is not anticipated in cerebral malaria.
  • Further research into BBB dynamics during CM and its effect on drug disposition is warranted.

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