Background: Malaria continues to be a major health concern and affects more than 200 million
people a year. Drugs currently used for treatment of malaria are increasingly rendered ineffectual
by the ongoing emergence of parasite resistance. For any new drugs, however, knowledge of their
membrane permeability is an essential pre-requisite for eventual use. Treatment failure and emergence
of resistance can occur as a result of reduced availability of the drug at the desired site of action. Cellbased
permeability assays such as Caco-2 cell monolayers serve as a model for predicting drug absorption
and efflux, and provide an estimate of drug bioavailability.
Objective: Here we have studied the bi-directional transport of new anti-malarial compounds, artemisone
and artemiside, as well as reference compounds, namely the known anti-malarial drug artemether,
and caffeine and atenolol.
Methods: The Caco-2 cell monolayer model was used to assess the membrane permeation properties of
these compounds, and to identify if they are subject to P-gp associated efflux, in the presence and absence
of verapamil. The effect of piperine on the transport of the compounds that were identified to be
P-gp substrates was also assessed. Samples withdrawn from the acceptor chambers at pre-determined
time intervals were analysed by means of high-performance liquid chromatography (HPLC).
Results: Transport results in terms of the absorptive direction revealed that artemisone and artemether
had low absorption rates relative to the reference compounds. It was further demonstrated that artemisone
is slightly effluxed, and although both artemether and artemiside were susceptible to P-gp mediated
efflux, it appears that other efflux proteins may also be involved.
Conclusion: The low permeability of anti-malarial drugs must be borne in mind during development of
effective dosage regimens of new drugs.