Modeling of controlled release of aspirin derivatives from human erythrocytes

The transport of aspirin (ASP) and its derivatives (m- or p-acetoxybenzoic acid (m- or p-AcOHBA), o-propionyloxybenzoic acid (PrOHBA), o-butyryloxybenzoic acid (BuOHBA), o-acetoxyhippuric acid (AcOHPA), and o-acetoxy-N-benzoyl-beta-alanine (AcONBA)) through human erythrocyte membrane was investigated. ASP derivatives were transported into the erythrocytes where they were hydrolyzed and then released, although the derivatives varied in the rate of transport. In different binding positions, the hydrolyzed derivatives were released rapidly in the order of p- > m- > o-AcOHBA (ASP). The rates of derivatives were accelerated by lengthening of the side chain of the acetoxyl group (BuOHBA > PrOHBA > ASP). The rate of release of o-, m- or p-AcOHBA, BuOHBA and PrOHBA was related to hydrolysis rate in erythrocytes but not to partition coefficient (log P). In different amino acids in a carboxyl group of ASP, the release of AcONBA was slower and about 2 h was required to attain equilibrium. The release of AcOHPA was also slower and increased gradually during an incubation of 3 h. The rate of release of AcOHPA and AcONBA was not related to hydrolysis rate in the erythrocytes. The rates were equivalent values with the predicted values calculated by log P of tested drugs. It was suggested from these results that ASP derivatives were able to control the release from human erythrocytes.