Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. I. 2-Phenylpropionic acid disposition.

The disposition of 2-phenylpropionic acid (2PPA) enantiomers has been studied in 12 rabbits with normal renal function (control) and in 6 rabbits with renal dysfunction. In control animals a mean (S.E.M.) of 0.23 (0.02) of R-2PPA was inverted to S-2PPA, and the distribution volumes for unbound S- and R-2PPA were 0.30 (0.02) and 0.62 (0.07) liters/kg, respectively, but there was no evidence of stereoselectivity in the glucuronidation of R- or S-2PPA. A model was developed that predicted the fraction of the 2PPA in plasma present as unbound S-2PPA upon infusion of racemic 2PPA to steady state. The mean (S.E.M.) observed fraction was 0.69 (0.01) and the predicted fraction was 0.66 (0.03). Comparing the mean parameters of 2PPA disposition in renal dysfunction with those in the same animals during a control study, the fraction of R-2PPA undergoing inversion increased by 350%, the clearance of unbound S-2PPA decreased to 25% and the unbound clearance of R-2PPA by processes other than inversion decreased to 9% of the control means. These changes are consistent with the effects of renal dysfunction on acyl-glucuronide futile cycles for both R- and S-2PPA. Using the above data it can be calculated that, in an animal with severe renal dysfunction, upon an infusion of racemic 2PPA to steady state the concentration of the unbound S-enantiomer would be 5.6 times that in a control animal.