Premium
Effect of clofibrate on the chiral inversion of ibuprofen in healthy volunteers
Author(s) -
Scheuerer Stefan,
Hall Stephen D.,
Williams Kenneth M.,
Geisslinger Gerd
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90150-3
Subject(s) - clofibrate , ibuprofen , chemistry , metabolite , pharmacokinetics , metabolism , endocrinology , medicine , pharmacology , biochemistry
Objectives To determine the influence of the hypolipidemic drug clofibrate on the stereoselective metabolism of ibuprofen in humans. Methods Healthy male subjects ( n = 12) ingested a dose of 400 mg pseudoracemic ibuprofen (200 mg R ‐ibuprofen, 160 mg S ‐ibuprofen, and 40 mg 13 C‐ S ‐ibuprofen) on two occasions after either pretreatment with clofibrate (2 gm/day over 1 week) or no pretreatment in a randomized order. Results When subjects were pretreated with clofibrate, clearances of R ‐ibuprofen and 13 C‐ 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 increase was similarly reflected in the clearance by inversion of R ‐ibuprofen (control, 36.0 ml/min; treated, 118.8 ml/min; p < 0.01), as well as 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 13 C‐ S ‐ibuprofen (11.8 versus 10.6 L/min, respectively). The fractional 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 fractional inversion was calculated from the plasma concentration‐time data for the unmetabolized drug. Conclusions Clofibrate altered the stereoselective disposition of ibuprofen in healthy volunteers by increased formation of R ‐ibuprofenoyl‐coenzyme A rather than by an effect on oxidative metabolism of ibuprofen. This interaction has potential therapeutic implications. Clinical Pharmacology & Therapeutics (1998) 64 , 168–176; doi: