Human pharmacokinetics of ibuprofen enantiomers following different doses and formulations: intestinal chiral inversion.

The influences of absorption rate and dosage size on the pharmacokinetics of ibuprofen (IB) enantiomers were studied in six healthy subjects. Rapidly absorbed solutions (50, 100, 200, 400, 600, and 1200 mg) and regular 600-mg tablets of racemic IB were given orally, and plasma concentration-time courses of the enantiomers were followed. Solutions were absorbed faster (tmax less than 0.25 h) than the tablet (tmax = 2.17 +/- 1.17 h). While the S:R AUC ratios were unaffected by increasing the dose, they were significantly greater after the tablet (1.35 +/- 0.14) as compared with the solutions (1.15 +/- 0.16 to 1.24 +/- 0.26). This indicates a greater extent of chiral inversion for the tablet, perhaps due to a longer residence time in the gut, thereby allowing more presystemic inversion. To test this hypothesis, R-IB was incubated at 37 degrees C in the presence of excised segments of human ileum and colon obtained from three patients. Chiral inversion was evident in all segments. After 3 h, the extent of inversion ranged from 20.0 to 33.0%. In addition, incubation resulted in the formation of up to 23.3 and 13.0% of acylglucuronides of S- and R-IB, respectively. In all subjects, the AUC-dose relationships were nonlinear, indicating a gradual increase in the clearance of both enantiomers due, perhaps, to a parallel saturation of plasma protein binding sites. In humans, the chiral inversion of IB is not influenced by the dosage size but is enhanced by prolongation of the residence time in the intestine.