Disposition of CS-670, a novel nonsteroidal anit-inflammatory drug, and its metabolites in healthy human volunteers.

CS-670, a novel nonsteroidal anti-inflammatory drug, is a racemic prodrug. Plasma concentrations and urinary excretion of CS-670 and its metabolites were determined in experimental subjects after oral administration at a single 120 mg dose. CS-670 and four metabolites, the saturated ketone (M-A), unsaturated-alcohol (M-B), cis-alcohol (M-C), and trans-alcohol (M-D), were quantitated by GC-MS. The major metabolites in human plasma were M-B, M-C, and M-D and their terminal half-lives (t1/2) were 0.9, 2.6, and 1.2 h, respectively. The total recovery in the urine was 26% of the dose, but unchanged CS-670 accounted for less than 2% over a 48 h period. In addition, the absolute configurations of the metabolites were examined by HPLC after derivatization with chiral reagents. It was found that the configuration of the propionic acid moiety of the metabolites, M-B, M-C, and M-D, in human plasma, was rapidly inverted from (-)-(R) to the (+)-(S) configuration in stereoselective biotransformation. Furthermore, the configurations of the 1'- and 2'-carbons of M-C and M-D, were found to be (1'R, 2'S) and (1'R, 2'S), respectively. These results show that CS-670 is readily biotransformed by chiral inversion of the 2-arylpropionic acid moiety and stereoselective reduction of the alpha, beta-unsaturated ketone moiety in humans.