Epimerization of moxalactam by albumin and simulation of in vivo epimerization by a physiologically based pharmacokinetic model

We investigated the mechanism of epimerization (R to S or S to R) of moxala ctam in serum of rats, dogs, and humans. The epimerization of moxalactam oc curred in the serum of these animals, but not in the serum filtrate. The al bumin fraction of human serum purified by gel filtration catalysed the epim erization of moxalactam at an identical rate to serum, but other fractions (i.e., lipoproteins and globulins) showed slower epimerization. alpha(1)-ac id glycoprotein, which was eluted in the same fraction with albumin by G-20 0 gel filtration, did not epimerize moxalactam. The presence of 2 mM warfar in decreased the binding of R- and S-moxalactam and decreased the epimeriza tion of moxalactam in human serum. These results demonstrate moxalactam was epimerized on the warfarin binding site on albumin in serum. Additionally, a physiologically based pharmacokinetic model shows that the epimerization of moxalactam after administration in dogs is simulated by the epimerizati on in serum. Chirality 11:309-315, 1999. (C) 1999 Wiley Liss, Inc.