EFFECT OF CLOFIBRATE ON THE CHIRAL INVERSION OF IBUPROFEN IN HEALTHY-VOLUNTEERS

Objectives: To determine the influence of the hypolipidemic drug clofi brate on the stereoselective metabolism of ibuprofen in humans. Method s: Healthy male subjects (n = 12) ingested a dose of 400 mg pseudorace mic ibuprofen (200 mg R-ibuprofen, 160 mg S-ibuprofen, and 40 mg C-13- S-ibuprofen) on two occasions after either pretreatment with clofibrat e (2 gm/day over 1 week) or no pretreatment in a randomized order. Res ults: When subjects were pretreated with clofibrate, clearances of R-i buprofen and 13C-S-ibuprofen increased significantly from 55.0 and 66. 4 ml/min to 186.2 and 106.7 ml/min (p < 0.01), respectively. This incr ease was similarly reflected in the clearance by inversion of R-ibupro fen (control, 36.0 ml/min; treated, 118.8 ml/min; p < 0.01), as well a s in the clearance by noninversion (control, 19.0 ml/min; treated, 67. 4 ml/min; p < 0.01). Unbound clearance values significantly increased for R-ibuprofen (control, 19.5 L/min; treated, 38.7 L/min) but not for C-13-S-ibuprofen (11.8 versus 10.6 L/min, respectively). The fraction al inversion of ibuprofen calculated from the urinary metabolite data was increased after clofibrate pretreatment (clofibrate group, 66.4%; control, 53.5%; p < 0.01). However, this was not evident when fraction al inversion was calculated from the plasma concentration-time data fo r the unmetabolized drug. Conclusions: Clofibrate altered the stereose lective disposition of ibuprofen in healthy volunteers by increased fo rmation of R-ibuprofenoyl-coenzyme A rather than by an effect on oxida tive metabolism of ibuprofen. This interaction has potential therapeut ic implications.