Kinetics and thermodynamics of chloroquine and hydroxychloroquine transport across the human erythrocyte membrane.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have almost identical molecular volumes but showed very different permeability characteristics. The permeability coefficient for the unionised species of CQ (2.0 cm/sec at 25 degrees) was about fifty times that of HCQ (0.039 cm/sec at 25 degrees), but the apparent activation energy for transport (85 kJ/mol for CQ, 81 kJ/mol for HCQ) was almost identical for the two drugs. The partition coefficient of CQ into various organic solvents was much higher than for HCQ, but the different permeability behaviour cannot be quantitatively explained by partitioning behaviour into hexane or octanol, two solvents commonly used to mimic the membrane interior. A comparison of permeability and partitioning characteristics suggests that the barrier phase for these drugs within the membrane can be modelled by a mixed solvent of 5% octanol in hexane. The results suggest that interactions with hydrogen bonding groups within the membrane are important in the membrane transport of these drugs, and that the membrane does not behave functionally as a simple hydrocarbon barrier.