An evaluation of ibuprofen bioinversion by simulation.

Using a pharmacokinetic model recently proposed to explain ibuprofen disposition in man, plasma concentrations of pure ibuprofen enantiomers were simulated following oral administration of (-)-(R)-ibuprofen, (+)-(S)-ibuprofen, or rac-ibuprofen. Simulated and literature values for AUC's were used to compare S/R ratios for different cases of the model and for different methods of calculating the fraction of R bioinverted to S. Numerical simulation using STELLA confirmed previous results for different cases of bioinversion. Simulated S/R AUC ratios, for administration of the racemate, ranged from 4.0 (presystemic bioinversion) to 1.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 1.53 +/- 0.2 for administration of the racemate; therefore, systemic bioinversion was concluded to be representative of ibuprofen disposition. Additional simulations of S/R AUC ratios, for administration of (-)-(R)-ibuprofen only, ranged from 1.5 (presystemic bioinversion) to 0.66 (systemic bioinversion). Literature values for S/R AUC ratios averaged 0.50 +/- 0.9 for administration of (-)-(R)-ibuprofen only, which again supported conclusions of systemic bioinversion. Using different equations for estimation of fraction of R inverted to S (FR----S), results based on simulated data were identical; however, FR----S values based on literature data were different. Therefore, assumptions made for different FR----S equations do not appear to be rigorous. Calculations of FR----S, based on literature data, averaged 0.52 overall, indicating bioavailability of (+)-(S)-ibuprofen may be similar for a 150 mg dose of (+)-(S)-ibuprofen compared to a 200 mg dose of racemate.