Stereoselective metabolism of 2-phenylpropionic acid in rat. II. Studies on the organs responsible for the optical isomerization of 2-phenylpropionic acid in rat in vivo.

The contribution of the liver and kidney to the optical isomerization of (R)-(-)-2-phenylpropionic acid (hydratropic acid (HTA] was examined by iv injection of racemic HTA (20 mg/kg) to nephrectomized and bile duct-ligated rats (NEBL-rats), eviscerated rats with nonfunctioning livers (EVIS-rats), rats with ligated bilateral ureters and bile ducts (BUBL-rats), and sham-operated rats. The decrease of (R)-(-)-enantiomer percentage of HTA in plasma of EVIS-rats from 53% (5 min) to 45% (60 min) clearly proved the contribution of the kidney on the optical isomerization of (R)-(-)-HTA in vivo. In NEBL-rats, the decrease of (R)-(-)-enantiomer percentage of HTA in plasma was only 2% in 55 min, but the (R)-(-)-enantiomer percentages of HTA acyl glucuronide (HTA-G) in plasma and liver at 1 hr after dosing were 40% and 30%, respectively. Therefore, the contribution of the liver on the isomerization was also suggested. Only a trace amount of HTA-G was detected in the EVIS-rats plasma and kidney, confirming the low glucuronic acid-conjugating activity of HTA in rat kidney. But, in the BUBL-rats, stereoselective hydrolysis of (R)-(-)-HTA-G in the kidney was suggested. Both the stereoselective glucuronidation of (S)-(+)-HTA and the stereoselective hydrolysis of (R)-(-)-HTA-G in rat liver might be responsible for the enrichment of (S)-(+)-HTA-G in the liver.