Ruwart: Ibuprofen stereoisomer hepatic clearance and distribution in normal and fatty in situ perfused rat liver

Ibuprofen is a 2-aryipropionic acid anti-inflammatory agent that undergoes stereoselective chiral inversion (R to S configuration) as well as oxidative metabolism in humans and rats. The present study was undertaken to define more clearly the role of the liver in ibuprofen stereoisomer clearance in both normal and disease states. Liver perfusion experiments were conducted with normal and fatty rat liver; chronic fatty liver was induced by nutritional deficiency and was used as a model of hepatotoxin-induced fatty liver in humans. Total (R)-ibuprofen clearance (CIRtI, chiral in-version-related clearance (CIR”), (S)-ibuprofen clearance (Cis) and hepatic distribution coefficients for each stereoisomer (KR and K) were calculated with a model that corrected for perfusate reservoir sampling. In both normal and fatty liver, CIR accounted for 60 % of C/At0t, but CIRt#{176}was 30 % lower in fatty liver than in normal liver (P <.001). CI was 40 % of CIR#{176}in normal liver and was not significantly different from the noninversion clearance of (R)-ibuprofen. CI was unchanged between normal and fatty liver and K5 was greater than KR in normal liver (P =.01) but not in fatty liver. The results indicate that the fatty liver condition stereoselectively affects (R)-ibuprofen clearance and eliminates preferential (S)-isomer hepatic distribution. Based on model sim-ulations, these effects are predicted to have minimal impact on total ibuprofen plasma levels or area-under-curve measurements following a dose of rac-ibuprofen unless CIRt0t is reduced by more than 50%. Ibuprofen [(RS)-2-(4-isobutylphenyl)propionic acid; Motri