Abstract
Chloroquine and hydroxy-chloroquine already established as anti-malarial and lupus drugs have recently gained renewed attention in the fight against the Covid-19 pandemic. Bio-mimetic HPLC methods have been used to measure the protein and phospholipid binding of the racemic mixtures of the drugs. The tissue binding and volume of distribution of the enantiomers have been estimated. The enantiomers can be separated using Chiralpak AGP HPLC columns. From the α-1-acid-glycoprotein (AGP) binding, the lung tissue binding can be estimated for the enantiomers. The drugs have a large volume of distribution, showed strong and stereoselective glycoprotein binding, medium-strong phospholipid-binding indicating only moderate phospholipidotic potential, hERG inhibition and promiscuous binding. The drug efficiency of the compounds was estimated to be greater than 2 % which indicates a high level of free biophase concentration relative to dose. The biomimetic properties of the compounds support the well-known tolerability of the drugs.
Highlights
Chloroquine (CQ) and hydroxy-chloroquine (HCQ) are well established for the treatment of malaria, rheumatoid arthritis, and lupus
The stereoselective binding to AGP did not result in significant differences in the estimated total plasma protein binding, lung tissue binding and volume of distribution
The retention time measurements are very reproducible on the biomimetic columns, but the absolute values of the calculated binding data originate from the error of the calibration line fit
Summary
Chloroquine (CQ) and hydroxy-chloroquine (HCQ) are well established for the treatment of malaria, rheumatoid arthritis, and lupus. During the Second World War, when millions of soldiers were taking CQ for malaria prevention, its beneficial effects were discovered in the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). When the resistance of CQ against malaria plasmids became apparent, the search for analogues resulted in the discovery of HCQ in 1945 [1]. In December 2019, an outbreak of pneumonia of unknown aetiology was reported in Wuhan, China [4,5].
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