Effect of absorption rate on pharmacokinetics of ibuprofen in relation to chiral inversion in humans

The effect of absorption rate on the pharmacokinetics of ibuprofen enantiomers was investigated in 12 healthy Han Chinese male volunteers following oral administration of immediate‐release (IR) and sustained‐release (SR) preparations containing racemic ibuprofen (rac‐ibuprofen). The area under the curve of the plasma concentration‐time curve (AUC; (mean ± s.d.) values for rac‐ibuprofen were 192.90 ± 43.47 for the SR preparation and 195.90 ± 31.69 μg h mL−1 for the IR preparation. AUC values for the enantiomers after administration of the SR formulation were 55.38 ± 17.79 and 92.51 ± 30.68 μg h mL−1 for R‐ and S‐ibuprofen, respectively, and were 65.94 ± 20.06 and 100.81 ± 32.28 μg h mL−1 for R‐ and S‐ibuprofen after administration of the IR preparation. These values did not differ significantly. Cmax values were significantly decreased with the SR preparation: 25.11 ± 5.71, 12.24 ± 3.79 and 12.38 ± 3.55 μg mL−1 for rac‐, R‐, and S‐ibuprofen, respectively, after administration of the SR preparation, vs 46.21 ± 8.20, 20.82 ± 5.90 and 23.46 ± 7.30 μg mL−1 for rac‐, R‐, and S‐ibuprofen, respectively, after administration of the IR preparation. Mean residence time was significantly increased: 7.01 ± 1.29, 5.52 ± 1.25 and 7.04 ± 1.30 h for rac‐, R‐, and S‐ibuprofen, respectively, after administration of the SR preparation vs 4.34 ± 0.89, 3.43 ± 0.64 and 4.51 ± 0.79 h for rac‐, R‐, and S‐ibuprofen, respectively, after administration of the IR preparation. AUC values for S‐ibuprofen were significantly larger than those for R‐ibuprofen in both preparations, indicating unidirectional chiral inversion. The S/R ratio of serum concentrations of enantiomers was 1.78‐fold higher at 6 h after administration of the SR preparation compared with the IR preparation (P < 0.01). These results indicate that ibuprofen undergoes pre‐systemic chiral inversion in parallel with a systemic process and that the clinical effects of rac‐ibuprofen in humans depend on the absorption rate.