Stereoselective Disposition of Ibuprofen Enantiomers in the Isolated Perfused Rat Kidney

Abstract

The renal clearance of ibuprofen enantiomer was studied separately in the isolated perfused rat kidney at initial perfusate concentrations of 10 µg/ml (n = 4) and 100 µg/ml (n = 4). Perfusate and urine samples were measured for R(–) and S( + )-ibuprofen using a stereospecific HPLC assay; urine samples were also analyzed after alkaline hydrolysis. Functional viability of the kidney was assured by determining the fractional excretion of glucose and glomerular filtration rate (GFR) at similar perfusion pressures. The clearance of ibuprofen was equivalent to the apparent formation clearance of conjugated enantiomer since unchanged ibuprofen could not be detected in the urine. At 10 and 100 µg/ml, the clearance (±SD) of R(–)-ibuprofen was 2.50 ± 1.28 and 2.19 ± 1.42 µl/min, respectively. At 100 µg/ml, the clearance of S( + )-ibuprofen was 0.805 ± 0.290 µl/min. The protein binding of ibuprofen was found to be concentration dependent and favored the R(–)-enantiomer. The excretion ratio (clearance corrected for free fraction and GFR) of R(–)-ibuprofen was 0.398 ± 0.209 and 0.295 ± 0.209 for perfusate concentrations of 10 and 100 µg/ml, respectively. The excretion ratio of S( + )-ibuprofen was 0.0886 ± 0.0335 for perfusate concentrations of 100 µg/ml. These results demonstrate that the sum of renal mechanisms involved for the clearance of R(–)- and S( + )-ibuprofen was net reabsorption. Ibuprofen was recovered in the urine solely as conjugated material and no evidence of R(–) to S( + ) conversion was observed. In addition, the data suggest that R(–)-ibuprofen is cleared through the kidney faster than its S( + )-enantiomer.