Cationomycin and monensin partition between serum proteins and erythrocytemembrane: Consequences for Na+ and K+ transport and antimalarial activities

The ionophore properties of cationomycin and monensin were studied on human erythrocytes by measuring Na+ influx by Na-23 MMR and concomitant K+ efflu x by potentiometry in the presence of increasing amounts of serum. Both ion currents (Na+ or K+) decreased linearly with the reciprocal of serum amoun t. The serum effects on ion currents were stronger with cationomycin than w ith monensin. Assuming this decreased transport activity was due to drug bi nding to serum proteins, a partition coefficient between the protein and th e membrane phase was determined for each ionophore by using a novel model. This partition coefficient is about 30 times higher for cationomycin than f or monensin; the same result was obtained with purified human serum albumin , indicating that albumin may be the major ionophore binding protein of ser um. In parallel, we also measured IC50 for 50% in vitro growth inhibition o f Plasmodium falciparum, the agent of malaria. In the presence of increasin g serum concentrations, the antimalarial activity was decreased for both io nophores. Serum effect was less severe for monensin than for cationomycin, in agreement with the weaker interaction of monensin with proteins as shown from the partition coefficient values. A correlation was established betwe en the ion transport currents (sodium and potassium) and the IC50 measured on P. falciparum in the presence of the various concentrations of serum. Th e relative value of the ion transport currents (expressed as percentage of control in absence of serum) can be indicative of the ionophore unbound fra ction in the medium. (C) 1999 Academic Press.